ORCID Profile
0000-0001-5094-098X
Current Organisation
University of South Australia
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Publisher: SAGE Publications
Date: 09-09-2008
Abstract: l-carnitine is an endogenous substance, vital in the transport of fatty acids across the inner mitochondrial membrane for oxidation. Disturbances in carnitine homeostasis can have a significant impact on human health therefore, it is critical to define normal endogenous concentrations for l-carnitine and its esters to facilitate the diagnosis of carnitine deficiency disorders. This study was conducted to determine the normal concentrations of a number of carnitines in healthy adults using three analytical methods. The impact of age and gender on carnitine concentrations was also examined. Blood s les were collected from 60 healthy subjects of both genders and various ages. Plasma s les were analysed for endogenous carnitine concentrations by radioenzymatic assay, high-performance liquid chromatography and electrospray tandem mass spectrometry. Precision and accuracy of results obtained for each assay were within acceptable limits. Average endogenous concentrations obtained from the three analytical methods in this study were in the range of 38–44, 6–7 and 49–50 μmol/L for l-carnitine, acetyl-l-carnitine and total carnitine, respectively. Comparison of results between the genders indicated that males had significantly higher endogenous plasma l-carnitine and total carnitine concentrations than females. Age was found to have no impact on plasma carnitine concentrations. These results are useful in the evaluation of biochemical or metabolic disturbances and in the diagnosis and treatment of patients with carnitine deficiency.
Publisher: Wiley
Date: 2001
DOI: 10.1002/JLCR.450
Publisher: Oxford University Press (OUP)
Date: 03-05-2011
DOI: 10.1111/J.2042-7158.2011.01283.X
Abstract: The aim of this study was to assess the potential of a novel delivery device for administering drugs that suffer from a high degree of first-pass metabolism. A tri-layered buccal mucoadhesive patch, comprising a medicated dry tablet adhered to a mucoadhesive film, was prepared and characterized by its physicochemical properties and mucoadhesive strength. Nicotine was used as a model drug for the characterization of drug release and drug permeation. The influence of different adsorbents on the release of nicotine base from the patches was evaluated in vitro. Different molecular forms of nicotine (base and complex salt) were evaluated for their effect on release performance and permeation in vitro. Results demonstrated acceptable physicochemical and mucoadhesive properties for the tri-layered patch. Rapid release of nicotine was observed when nicotine base was incorporated with calcium sulfate dihydrate as the adsorbent. Patches incorporating nicotine base showed distinct advantages over those containing nicotine polacrilex, in terms of drug release (complete drug release achieved at 30 vs 60 min) and transmucosal permeation (37.28 ± 4.25 vs 2.87 ± 0.26% of the dose permeating through mucosa within 120 min). The novel tri-layered patch can effectively adhere to, and deliver an active ingredient through the buccal mucosa, confirming its potential for buccal mucoadhesive drug delivery.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 10-2008
Abstract: In humans, mycophenolic acid (MPA) is metabolized primarily by glucuronidation in the liver to mycophenolate ether glucuronide (MPAGe) and mycophenolate acyl glucuronide (MPAGa). We have previously reported that in perfused livers of TR(-) rats (lacking the Mrp2 transporter), the clearance and hepatic extraction ratio of MPA were significantly lower compared with control Wistar rats, suggesting a difference in the capacity of the TR(-) rats to metabolize MPA in situ. There is very little information regarding the phase II metabolic capabilities of TR(-) rats therefore, the aim of this study was to investigate the in vitro glucuronidation of MPA in Wistar and TR(-) rat liver microsomal protein. A second aim was to determine whether MPAGa, cyclosporine (CsA), and/or its metabolites AM1, AM1c, and AM9 inhibit the metabolism of MPA to MPAGe in rat liver microsomes. MPAGe formation rates by Wistar and TR(-) microsomes were 0.48 and 0.65 nmol/min/mg, respectively (p = 0.33). K(m) values for control and TR(-) microsomes were 0.47 and 0.50 mM, respectively (p = 0.81). The mean (S.E.M.) ratios of MPAGe formation by Wistar rat liver microsomes incubated with 50 microM MPA plus inhibitor versus 50 microM MPA alone were MPAGa 1.2 (0.1), CsA 0.7 (0.1) (p < 0.05), AM1 2.2 (0.3) (p < 0.05), AM1c 1.2 (0.2), and AM9 1.0 (0.2). Our results suggest that lower in situ glucuronidation of MPA in TR(-) rats may be because of inhibition of glucuronidation by endogenous and exogenous compounds that accumulate in the transporter-deficient rat. Whereas CsA inhibits glucuronidation of MPA, its metabolite AM1 enhances MPAGe formation by rat liver microsomes.
Publisher: Bentham Science Publishers Ltd.
Date: 09-2000
Abstract: Acyl glucuronides are a unique class of electrophilic metabolites, capable of non-enzymatic reactions including acylation and/or glycation of endogenous macromolecules, hydrolysis to reform the parent aglycone, and intra-molecular rearrangement. Three human UDP-glucuronosyltransferases (UGTs) catalyzing the hepatic glucuronidation of carboxylic acid drugs have been identified, UGT1A3, UGT1A9 and a UGT2B7 variant. Within the liver, acyl glucuronides also undergo enzymatic hydrolysis by beta-glucuronidase and esterases which, like the UGTs, are located in the endoplasmic reticulum. In addition, the liver also transports acyl glucuronides between the sinusoidal circulation and bile. Due to their polarity, membrane transport of acyl glucuronides is carrier-mediated, resulting in the establishment of significant concentration gradients between sinusoidal circulation, hepatocyte and bile, in the order of 1:50:5,000 in these compartments, respectively. As a result of exposure to high acyl glucuronide concentrations, the liver is a major target of protein adduct formation. Dipeptidylpeptidase IV, UGTs and tubulin have been identified as intra-hepatic targets of adduct formation by acyl glucuronides. Adduct formation results in altered protein activity and potentially contributes to hepatotoxicity. Hepatic protein adducts are also immunogenic and may cause immune mediated cytotoxicity. Both intra- and extra-hepatic exposure to acyl glucuronides depends not only on the efficiency of glucuronidation and hydrolysis by the liver, but also on the efficiency of the hepatic membrane transport systems. Thus, changes in membrane transporter activities, as may occur due to saturation or drug-drug interactions, can significantly affect acyl glucuronide disposition, adduct formation and the disposition of parent aglycone, thereby affecting clinical efficacy and toxicity of acyl glucuronide forming drugs.
Publisher: Springer Science and Business Media LLC
Date: 06-2004
DOI: 10.1023/B:PHAM.0000029287.56914.42
Abstract: To investigate the effects of potential inhibitors of membrane transport on the tubular secretion of AM188, an antiviral guanosine analog, in the isolated perfused rat kidney (IPK). AM188 was administered to the IPK perfusate as a bolus/infusion regimen. In inhibitor groups, probenecid, p-aminohippuric acid (PAH), cimetidine, or nitrobenzylthioinosine was added to the perfusing medium. In control IPKs, the ratio of renal clearance of AM188 (CLR) to GFR was 7.7 +/- 0.51 (mean +/- SD). The CL(R)/GFR ratio for AM188 was 6.20 +/- 0.41*, 2.85 +/- 0.20*, 1.45 +/- 0.07*, and 0.80 +/- 0.01* when the concentration of probenecid in perfusate was 10, 50, 100, and 1000 microM, respectively (*p < 0.05 compared to control group) the ratio was 7.71 +/- 0.38, 6.02 +/- 0.42*, 1.71 +/- 0.15*, and 0.91 +/- 0.07* for the PAH group and 6.42 +/- 1.70*, 5.33 +/- 1.53*, 3.16 +/- 0.81*, and 1.21 +/- 0.20* for the cimetidine group when the concentrations were 10, 100, 1000 and 10,000 microM, respectively and the ratio was 5.33 +/- 0.21* when the concentration of nitrobenzylthioinosine was 5 microM. These results suggest that renal tubular secretion of AM188 involves organic anion and cation transport systems.
Publisher: Wiley
Date: 15-05-2007
Publisher: Wiley
Date: 26-04-2021
DOI: 10.1111/BCP.14856
Abstract: The consumption of caffeine has been linked to osteoporosis, believed to be due to enhanced bone resorption as a result of increased calcium excretion in the urine. However, the amount of calcium in the urine may not necessarily reflect the true effect of caffeine on calcium clearance. This study therefore examined the impact of high‐dose, short‐term caffeine intake on renal clearance of calcium, sodium and creatinine in healthy adults. In a double‐blind clinical study, participants chewed caffeine ( n = 12) or placebo ( n = 12) gum for 5 minutes at 2‐hour intervals over a 6‐hour treatment period (800 mg total caffeine). Caffeine increased renal calcium clearance by 77%. Furthermore, the effect was positively correlated with sodium clearance and urine volume, suggesting that caffeine may act through inhibition of sodium reabsorption in the proximal convoluted tubule. This study confirmed that caffeine does increase renal calcium clearance and fosters further investigation into safe consumption of caffeine.
Publisher: Oxford University Press (OUP)
Date: 04-11-2014
DOI: 10.1093/JAC/DKU430
Abstract: The determination of dosing regimens for the treatment of malaria is largely empirical and thus a better understanding of the pharmacokinetic harmacodynamic properties of antimalarial agents is required to assess the adequacy of current treatment regimens and identify sources of suboptimal dosing that could select for drug-resistant parasites. Mefloquine is a widely used antimalarial, commonly given in combination with artesunate. Mefloquine pharmacokinetics was assessed in 24 healthy adults and 43 patients with Plasmodium falciparum malaria administered mefloquine in combination with artesunate. Population pharmacokinetic modelling was conducted using NONMEM. A two-compartment model with a single transit compartment and first-order elimination from the central compartment most adequately described mefloquine concentration-time data. The model incorporated population parameter variability for clearance (CL/F), central volume of distribution (VC/F) and absorption rate constant (KA) and identified, in addition to body weight, malaria infection as a covariate for VC/F (but not CL/F). Monte Carlo simulations predict that falciparum malaria infection is associated with a shorter elimination half-life (407 versus 566 h) and T>MIC (766 versus 893 h). This is the first known population pharmacokinetic study to show falciparum malaria to influence mefloquine disposition. Protein binding, anaemia and other factors may contribute to differences between healthy in iduals and patients. As VC/F is related to the earlier portion of the concentration-time profiles, which occurs during acute malaria, and CL/F is more related to the terminal phase during convalescence after treatment, this may explain why malaria was found to be a covariate for VC/F but not CL/F.
Publisher: Springer Science and Business Media LLC
Date: 04-1995
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.CLINTHERA.2014.06.037
Abstract: This study compared the pharmacokinetics of a single dose of 1% testosterone solution after application to the inner arm or the axilla as application sites for transdermal testosterone therapy. Healthy, not pregnant, premenopausal women, 18 to 45 years of age with a body mass index of 20 to 28 kg/m(2) were enrolled into a single-center, open-label, randomized, 2-way crossover study. Serum total testosterone (TT), free testosterone (fT), and sex hormone binding globulin concentrations were measured. Pharmacokinetic parameters determined from serum TT and fT included area under the serum concentration versus time curve from time zero (pre-dose) until 72 hours post-dose (AUC0-72), Cmax, and Tmax. Descriptive statistics were performed on serum concentrations of TT and fT for each site. ANOVA was performed on AUC0-72 and Cmax. A single-dose application of 1% testosterone solution to the inner arm and the axilla produced clear increases in TT and fT. Slower and lower increases in TT and fT were observed after treatment to the inner arm. Based on baseline-corrected AUC versus time curves, the bioavailability of 1% testosterone solution was increased 2-fold for the axilla compared with the inner arm. The absorption of a 1% testosterone solution was significantly greater after application to the axilla than to the inner arm. Study number DDS16 Australian Therapeutic Goods Administration, CTN 2005/158.
Publisher: International Pharmaceutical Federation (FIP)
Date: 03-2006
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.LFS.2006.09.008
Abstract: This study was designed to assess the cardioprotective effect of isosteviol on rats with heart ischemia-reperfusion (IR) injury and to explore the mechanism of action of the compound. Sprague Dawley rats were ided into 8 groups (n=10-12): a sham-operated control and 7 ischemia-reperfusion groups (IR control, 3 isosteviol pre-treated (0.5, 1.0 and 2.0 mg kg(-1)), ligustrazine pre-treated, 5-hydroxydecanoate (5-HD) pre-treated and 5-HD+ isosteviol pre-treated groups). IR was produced by occluding the left coronary artery for 30 min followed by re-opening the artery for 90 min. The compounds under investigation were administered intravenously 10 min prior to occluding the artery. Hemodynamic parameters (+/-dp/dt(max), LVSP, LVDevP, MAP), heart rate, ventricular tachycardia (VT) and ventricular fibrillation (VF) were determined during the IR period. The myocardial infarct size, activities of serum lactate dehydrogenase and creatine kinase were determined at the end of the experiment. In the isosteviol pre-treated groups, the hemodynamic parameters were improved and the myocardial infarct size, the activities of serum enzymes, and the incidences of VT and VF were all decreased when compared to the control group. These effects of isosteviol were similar to that of a traditional cardioprotective agent, ligustrazine. The 5-HD+ isosteviol group displayed parameters that were between those in the equivalent isosteviol pre-treated group and the IR control group. In conclusion, damage due to a standard rat heart IR injury was reduced by pretreatment with intravenous isosteviol, and this effect was partly attenuated by a mitochondrial ATP-sensitive potassium channel blocker, 5-HD.
Publisher: Springer Science and Business Media LLC
Date: 1989
DOI: 10.1007/BF00558161
Abstract: We present a case report of a patient with a suspicious ileal carcinoid tumour. Clinical examination as well as computer tomography (CT) scan suggested a tumour. Octeotride scan showed uptake in the same bowel loop reported as pathological in CT. The patient underwent surgery and biopsy which reported Crohn's disease (CD). The interest in the case is due to the fact that this is, to the best of our knowledge, the second report of Crohn's disease as a cause of false positive octeotride scan. Unfortunately, no somatostatin receptors could be found in the s le, so further studies should be performed.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 02-02-2010
Abstract: Clinical observation of a synergistic effect of ketamine on morphine analgesia remains controversial. Although a pharmacodynamic basis for an interaction has been explored in animal and clinical studies, the possibility of a pharmacokinetic mechanism has not been investigated. Whereas both morphine and morphine-6-glucuronide are effective analgesics, morphine-3-glucuronide (M3G) lacks activity. Thus, changes in the metabolism and disposition of morphine may result in an altered response. First, we investigated the interaction between morphine and ketamine in the isolated perfused rat liver preparation. The clearance of morphine was decreased from 16.8 +/- 4.6 ml/min in the control period to 7.7 +/- 2.8 ml/min in the ketamine-treatment period, with the formation clearance of M3G decreasing from 8.0 +/- 4.1 ml/min to 2.1 +/- 1.1 ml/min. Fractional conversion of morphine to M3G was significantly decreased from 0.46 +/- 0.17 in the control period to 0.28 +/- 0.14 upon the addition of ketamine. The possible mechanism of the interaction was further investigated in vitro with rat liver microsomes as the enzyme source. The formation of M3G followed single-enzyme Michaelis-Menten kinetics, with a mean apparent K(m) of 2.18 +/- 0.45 mM and V(max) of 8.67 +/- 0.59 nmol/min/mg. Ketamine inhibited morphine 3-glucuronidation noncompetitively, with a mean K(i) value of 33.3 +/- 7.9 microM. The results demonstrate that ketamine inhibits the glucuronidation of morphine in a rat model.
Publisher: Wiley
Date: 03-2009
DOI: 10.1002/J.2055-2335.2009.TB00705.X
Abstract: The role of in idual hepatic cytochrome P450 (CYP) enzymes in drug metabolism and the factors that modulate CYP activity are becoming increasingly well understood. These advances have resulted in a better understanding of drug‐drug and drug‐ food interactions and an enhanced capacity to predict drug interactions that may occur with new drugs. This final article in the series describes the issues and principles that are important in identifying and assessing drug interactions that involve CYP enzymes.
Publisher: Elsevier BV
Date: 12-1320
DOI: 10.1016/0742-8413(90)90142-V
Abstract: 1. A study has been made of the potency of a number of dopamine antagonists to inhibit dopamine-induced secretion from the cockroach salivary gland in vitro. 2. Chlorpromazine (0.5-5 microM), SCH23390 (10-100 microM), haloperidol (10-100 microM) and metoclopramide (2 mM) competitively inhibited the secretory response to dopamine. In contrast (+/-)sulpiride (1-100 microM) and domperidone (1-100 microM) had no effect on either basal or dopamine-induced secretion. 3. Apparent dissociation constants (KDapp) were obtained using a 'three point assay'. The rank order of potency (KDapp in parentheses) was as follows: chlorpromazine (0.2 microM) greater than SCH23390 (2.2 microM) greater than haloperidol (17.5 microM) much greater than metoclopramide (1.2 mM). 4. It is concluded that the receptor mediating dopamine-induced secretion in the cockroach salivary gland is similar to the D1/DA1 dopamine receptor and distinct from the D2/DA2 receptor found in mammalian systems.
Publisher: Informa UK Limited
Date: 06-2011
DOI: 10.2147/IJN.S19151
Publisher: BMJ
Date: 20-08-2012
Publisher: Oxford University Press (OUP)
Date: 12-2003
Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit the renal tubular secretion of methotrexate. However, the relative contribution of the active S- and inactive R-enantiomers is unknown. This study examined the effect of racemic ketoprofen and its enantiomers on the renal disposition of methotrexate in the isolated perfused rat kidney (IPK). Nineteen kidneys were ided between a control and three treatment groups. Controls were perfused with methotrexate alone (25 μg mL−1, n = 5) over three 30-min periods. Treatment groups were perfused with methotrexate (25 μg mL−1) for the first period, followed by a second period of methotrexate (25 μg mL−1) plus R- (n = 5), S- (n = 5) or RS-ketoprofen (n = 4) at 25 μg mL−1, and a third period of methotrexate (25 μg mL−1) plus R-, S- or RS-ketoprofen (50 μg mL−1). Perfusate and urine were collected over 10-min intervals. Methotrexate was measured by HPLC and its binding in perfusate by ultrafiltration. The clearance ratio (CR) for methotrexate was obtained by iding the renal clearance by the product of its fraction unbound and the glomerular filtration rate. During control experiments, there was no significant change in the CR over 90 min. R-, S- and RS-ketoprofen at 50 μg mL−1 reduced the CR of methotrexate significantly, but there was no difference between the three groups. While the enantiomers of ketoprofen reduced the renal excretion of methotrexate, the interaction was not enantioselective.
Publisher: Wiley
Date: 04-08-2007
DOI: 10.1111/J.1463-1326.2006.00630.X
Abstract: The aim of this study was to test the effect of isosteviol on blood glucose and insulin levels during the intravenous glucose tolerance test (IVGTT) in Wistar and Zucker diabetic fatty (ZDF) rats. ZDF rats were ided into a control and three isosteviol treatment (1, 5 and 10 mg/kg) groups. Wistar rats were ided into a control group and an isosteviol treatment group (10 mg/kg). The rats were fasted for 12 h prior to infusion of isosteviol and glucose (1.0 g/kg). Blood s les were taken at 0, 5, 15, 30, 60, 90 and 120 min after the injection of glucose. Glucose concentrations were determined by the glucose oxidase method, and plasma insulin was analysed by radioimmunoassay. The area under the curve (AUC) of the net change in plasma glucose concentration was used to compare the isosteviol treatment and control groups. In ZDF rats, isosteviol at 5 and 10 mg/kg caused a significant (p < 0.05) reduction in the AUC of glucose during the IVGTT. However, isosteviol did not increase plasma insulin concentrations in ZDF rats. In Wistar rats, isosteviol did not significantly affect plasma glucose or insulin levels during the IVGTT. Isosteviol exerts an antihyperglycaemic effect during IVGTT in ZDF rats but not in Wistar rats. Isosteviol has no significant effect on plasma insulin concentrations. The glucose-lowering effect of isosteviol may be due to changes in the sensitivity of peripheral tissues to insulin.
Publisher: Oxford University Press (OUP)
Date: 09-01-2006
DOI: 10.1093/NDT/GFK056
Abstract: Trimethylamine (TMA) is a short-chain tertiary aliphatic amine that is derived from the diet either directly from the consumption of foods high in TMA or by the intake of food high in precursors to TMA, such as trimethylamine-N-oxide (TMNO), choline and L-carnitine. The clinical significance of TMA may be related to its potential to contribute to neurological toxicity and 'uraemic breath' in patients with end-stage renal disease (ESRD). Concentrations of TMA and TMNO in plasma from 10 healthy adults (not on haemodialysis) and 10 adults with ESRD undergoing haemodialysis (pre- and post-dialysis) were determined by gas chromatography-mass spectrometry. The concentrations of TMA and TMNO in pre-dialysis plasma (1.39+/-0.483 and 99.9+/-31.9 microM, respectively) were significantly (P<0.05) higher than the corresponding levels in healthy subjects (0.418+/-0.124 and 37.8+/-20.4 microM, respectively). However, there were no significant differences between post-dialysis and healthy subject plasma concentrations. In the ESRD patients, there was a significant (P<0.05) reduction in plasma TMA (from 1.39+/-0.483 to 0.484+/-0.164 microM) and TMNO (from 99.9+/-31.9 to 41.3+/-18.8 microM) during a single haemodialysis session. TMA and TMNO accumulate between haemodialysis sessions in ESRD patients, but are efficiently removed during a single haemodialysis session.
Publisher: Springer Science and Business Media LLC
Date: 21-08-2015
DOI: 10.1007/S40261-015-0312-8
Abstract: Piperaquine-dihydroartemisinin combination therapy has established efficacy for the treatment of malaria however, a more comprehensive understanding of the pharmacokinetic properties and factors contributing to inter- and intra-in idual variability is critical to optimize clinical use. This study assessed the effects of food on the pharmacokinetics of combination piperaquine-dihydroartemisinin administration in healthy volunteers. This was an open-label, single-dose, parallel-group study. Participants were randomly allocated to receive oral piperaquine-dihydroartemisinin either after an overnight fast or immediately after a standardized, high-fat, high-calorie meal. Blood s les were collected for analysis of plasma piperaquine and dihydroartemisinin concentrations, which were utilized for calculation of pharmacokinetic parameters, using a standard model-independent approach. Consumption of a high-fat, high-calorie meal resulted in substantial increases in the extent of exposure to piperaquine (ratio between area under the plasma concentration-time curve [AUC] values from 0 to 168 h in the fed and fasted states [AUC0-168 h FED/AUC0-168 h FASTED] = 299 %, 90 % confidence interval [CI] 239-374 %). This likely reflects an increase in the oral bioavailability of the drug, directly related to the fat content of the meal. Co-administration of food was also found to result in both delayed and enhanced absorption of dihydroartemisinin (ratio between AUC values from time zero to infinity in the fed and states [AUC∞ FED/AUC∞ FASTED] = 142 %, 90 % CI 113-178 % ratio between mean transit time [MTT] values in the fed and fasted states [MTTFED/MTTFASTED] = 135 %, 90 % CI 114-160 %). Although food was found to significantly impact on the pharmacokinetics of piperaquine and dihydroartemisinin, given the low fat content of standard meals within endemic regions and the anorexic effects of malaria infection, these results are unlikely to impact on the clinical utility of these drugs. However, co-administration of food with these anti-malarials by populations consuming a typical Western diet should be avoided to reduce the risk of toxic side effects. It is therefore a general recommendation that piperaquine-dihydroartemisinin not be administered within ±3 h of food consumption.
Publisher: Bentham Science Publishers Ltd.
Date: 10-2006
DOI: 10.2174/138920006778520589
Abstract: The vectorial movement of glucuronide conjugates from blood into bile can be an important elimination route for many drug metabolites, however the intrinsic hydrophilicity of those conjugates may conceptually act to reduce the overall efficiency of that process by limiting the flux of such conjugates across the sinusoidal membrane domain of hepatocytes. In this investigation, the hepatic disposition of the diastereomeric glucuronides of (R)- and (S)-2-phenylpropionic acid (a model "profen" compound) have been studied using the isolated perfused rat liver to establish whether a permeability barrier at the sinusoidal membrane domain (demonstrated previously for those conjugates) is of a sufficient magnitude to impact on the overall biliary excretion of these conjugates. Livers were perfused (30 mL/min) with perfusate containing either (R)-PPA, (S)-PPA, (R)-PPA-Glucuronide or (S)-PPA-Glucuronide in order to determine the dispositional profile of each glucuronide administered to the liver as both a preformed and an hepatically-generated metabolite. Once an apparent steady-state condition had been reached, infusion of test compound was ceased in order to establish the kinetics of the hepatic washout. The extent of biliary excretion of each glucuronide was dependent upon whether the glucuronide was presented to the liver as a preformed or hepatically-generated metabolite, and those differences, when analysed using a physiologically-based pharmacokinetic model, were consistent with the sinusoidal membrane acting as a barrier to the cellular entry of the glucuronides. Furthermore, that barrier was more pronounced for (R)-PPAG than it was for (S)-PPAG, suggesting that the hepatocellular uptake of the two diastereomers is stereoselective.
Publisher: Wiley
Date: 02-2005
Abstract: This was a preliminary feasibility study to assess the pharmacokinetics and acute safety of a single dose of orally inhaled testosterone via the AERx system, a novel handheld aerosol delivery system in postmenopausal women. Twelve postmenopausal women stabilized on oral estrogen therapy were treated with a single dose of testosterone (0.1, 0.2, or 0.3 mg) by inhalation. Plasma concentrations of sex steroids were measured between 1 and 360 minutes. Pulmonary and cardiovascular adverse events were monitored. Inhaled testosterone produced a dose-dependent increase in plasma total and free testosterone. At the highest dose (0.3 mg), total and free testosterone increased from baseline (mean +/- SD, 0.6 +/- 0.3 nmol/L, 2.5 +/- 1.0 pmol/L) to maximum levels of 62.6 +/- 20.4 nmol/L (total) and 168.2 +/- 50.2 pmol/L(free), occurring 1 to 2 minutes after dosing. A 2-compartment model best described the free and total testosterone pharmacokinetic profile. Dihydrotestosterone levels were higher than baseline at 60 minutes (P < .0002). Estradiol did not vary, but sex hormone binding globulin and albumin fell. There were no adverse events related to the treatment. Administration of inhaled testosterone is safe and achieves a supraphysiologic "pulse" kinetic profile of total and free testosterone with a rapid return to pretreatment levels.
Publisher: Informa UK Limited
Date: 11-03-2014
Publisher: Wiley
Date: 21-03-2011
DOI: 10.1111/J.1440-1630.2010.00888.X
Abstract: Grip strength is useful in clinical practice for the assessment of disease and/or rehabilitation progression. Brief maximal gripping is seldom required in everyday occupations, with repeated or sustained gripping at sub-maximal power more commonly involved. It has been proposed that assessment of both maximal hand-grip force and endurance is utilised. While the suitability of maximal contraction measures has been clearly established, the reliability and validity of other hand-grip indices have not been investigated. This study examined the reliability of various hand-grip indices and their validity in relation to distance walked during the six-minute walk test, a standardised exercise capacity test. Subjects undertook static sub-maximal (50%) and maximal force contraction hand-grip testing from which various indices were derived, and six-minute walk testing from which distance walked was determined. Testing was repeated on three separate occasions for determination of test-retest reliability. Pre- and post-fatigue maximal contraction measurements demonstrated excellent test-retest reliability and validity. Conversely, other hand-grip indices were shown to be unreliable and exhibited no relationship with distance walked and hence concurrent validity could not be established. Based on the results of this study, it is recommended that pre- and post-fatigue maximal contraction may be utilised for the assessment of client ability and progression due to their established validity and test-retest reliability. However, previously proposed measures of fatigue such as endurance (duration of sustained contraction), Strength Decrement Index and work performed (function of endurance and force of contraction) are unreliable and invalid and may have limited use in clinical practice.
Publisher: Springer Science and Business Media LLC
Date: 09-2012
DOI: 10.1007/BF03261931
Publisher: Wiley
Date: 11-2000
DOI: 10.1046/J.1365-2125.2000.00280.X
Abstract: Propionyl-L-carnitine (PLC) is an endogenous compound which, along with L-carnitine (LC) and acetyl-L-carnitine (ALC), forms a component of the endogenous carnitine pool in humans and most, if not all, animal species. PLC is currently under investigation for the treatment of peripheral artery disease, and the present study was conducted to assess the pharmacokinetics of intravenous propionyl-L-carnitine hydrochloride. This was a placebo-controlled, double-blind, parallel group, dose-escalating study in which 24 healthy males were ided into four groups of six. Four subjects from each group received propionyl-L-carnitine hydrochloride and two received placebo. The doses (1 g, 2 g, 4 g and 8 g) were administered as a constant rate infusion over 2 h and blood and urine were collected for 24 h from the start of the infusion. PLC, ALC and LC in plasma and urine were quantified by h.p. l.c. All 24 subjects successfully completed the study and the infusions were well tolerated. In addition to the expected increase in PLC levels, the plasma concentrations and urinary excretion of LC and ALC also increased above baseline values following intravenous propionyl-L-carnitine hydrochloride administration. At a dose of 1 g, PLC was found to have a mean (+/- s.d.) half-life of 1.09 +/- 0.15 h, a clearance of 11.6 +/- 0.24 l h-1 and a volume of distribution of 18.3 +/- 2.4 l. None of these parameters changed with dose. In placebo-treated subjects, endogenous PLC, LC and ALC underwent extensive renal tubular reabsorption, as indicated by renal excretory clearance to GFR ratios of less than 0.1. The renal-excretory clearance of PLC, which was 0.33 +/- 0.38 l h-1 under baseline condition, increased (P < 0. 001) from 1.98 +/- 0.59 l h-1 at a dose of 1 g to 5.55 +/- 1.50 l h-1 at a dose of 8 g (95% confidence interval for the difference was 2.18,4.97). As a consequence, the percent of the dose excreted unchanged in urine increased (P < 0.001) from 18.1 +/- 5.5% (1 g) to 50.3 +/- 13.3% (8 g). The renal-excretory clearance of LC and ALC also increased substantially after PLC administration and there was evidence for renal metabolism of PLC to LC and ALC. Intravenous administration of propionyl-L-carnitine hydrochloride caused significant increases in the renal excretory clearances of PLC, LC and ALC, due to saturation of the renal tubular reabsorption process - as a consequence there was a substantial increase with dose in the fraction excreted unchanged in urine. Despite the marked increase in the renal clearance of PLC, total clearance remained unchanged, suggesting a compensatory reduction in the clearance of the compound by non excretory routes.
Publisher: Oxford University Press (OUP)
Date: 11-1999
Abstract: Previous studies using the rat isolated perfused liver demonstrated that the hepatic disposition of morphine-3-glucuronide is membrane permeability-rate limited, and that the movement of the metabolite across hepatic sinusoidal and canalicular membranes is partly via carrier-mediated transport systems. As a consequence of the membrane permeability-limitation, the biliary excretion of hepatically-generated morphine-3-glucuronide is much more efficient than that of morphine-3-glucuronide reaching the liver via the vasculature. We have quantitated the cellular efflux kinetics (cell-to-blood and cell-to-bile) of morphine-3-glucuronide in the rat isolated perfused liver using a loading wash-out design. In the ‘loading’ phase, morphine was infused into the liver (2.7 μM) and the biliary excretion and sinusoidal efflux of morphine-3-glucuronide was assessed under steady-state conditions. Subsequently, the infusion was stopped and the concentration vs time profile of morphine-3-glucuronide in outflow perfusate (the wash-out phase) was determined. A physiologically-based pharmacokinetic model was used to determine the rate-constants for the movement of hepatically-generated morphine-3-glucuronide into the sinusoidal and canalicular spaces of the liver, and the associated membrane permeability terms. The mean (±s.d.) rate constants for the biliary excretion and sinusoidal efflux of morphine-3-glucuronide were determined to be 0.160±0.043 and 0.169 ± 0.068 min−1, respectively, and the corresponding membrane permeability parameters were 1.12 and 1.18 mL min−1, respectively. The sinusoidal membrane permeability term was significantly less than hepatic blood flow in the rat. The volume of distribution of hepatically-generated morphine-3-glucuronide (207.5 ± 74.8 mL) was found to be approximately 50-times the intracellular space of the rat liver, suggesting that hepatically-generated morphine-3-glucuronide accumulates within hepatocytes. The results indicate that hepatically-generated morphine-3-glucuronide undergoes intracellular accumulation, probably as a consequence of poor membrane permeability.
Publisher: Springer Science and Business Media LLC
Date: 2000
Abstract: To examine the disposition of fexofenadine in the isolated perfused rat liver and the influence of erythromycin and dibromosulphthalein (DBSP) on the hepatic uptake and biliary excretion of fexofenadine. Livers from four groups of rats were perfused in a recirculatory manner with fexofenadine HCl added as a bolus (125, 250, 500, or 1000 microg) to perfusate. Livers from another three groups of rats were perfused with 250 microg of fexofenadine HCl. With one group as control, erythromycin (4.0 microg/ml) or DBSP (136 microg/ml) was added to the perfusate of the other groups. In all experiments, perfusate and bile were collected for 60 min in addition, livers from the second experiment were retained for assay. Fexofenadine was determined in perfusate, bile, and homogenized liver by HPLC. The area under the curve (AUC) of fexofenadine was linearly related to concentration. It was unchanged from control (12,800 +/- 200 ng x h/ml) by erythromycin (14,400 +/- 2000 ng x h/ml), but was increased 95% by DBSP (25,000 +/- 2600 ng x h/ml, P <0.001). The ratios of the concentrations of fexofenadine in liver erfusate were decreased significantly by DBSP those for bile/liver were increased by erythromycin. Erythromycin reduced the canalicular transport of fexofenadine into bile, whereas DBSP reduced uptake across the sinusoidal membrane.
Publisher: Informa UK Limited
Date: 1995
DOI: 10.3109/00498259509061903
Abstract: 1. The effects of the administration of the anticancer and immunosuppressive drug, cyclophosphamide, to the rat on hepatic P4502D1 activity and content in the microsomal fraction have been examined. 2. Liver microsomes were obtained from male Hooded Wistar rats administered a single dose (i.p.) of saline or cyclophosphamide (200 mg/kg). Rats receiving cyclophosphamide were killed 1, 4, 7, 10 or 14 days after cyclophosphamide administration. The O-demethylation of dextromethorphan to dextrorphan was used to monitor 2D1 activity. 3. The mean Vmax for dextrorphan formation was reduced significantly (p < 0.0001) 7, 10 and 14 days after cyclophosphamide administration compared with the control group (control, 0.32 +/- 0.07 7-day, 0.20 +/- 0.08 10-day, 0.11 +/- 0.02 and 14-day group, 0.15 +/- 0.02 nmol/mg/min). 4. Western blotting revealed that there was a significant reduction (p < 0.0005) in the microsomal relative 2D1 content 10 days after cyclophosphamide administration compared with the control group (control, 1.25 +/- 0.44 and 10-day group, 0.65 +/- 0.14). 5. The activity of reduced nicotinamide adenine dinucleotide phosphate P450 reductase was significantly reduced (p < 0.0001) 7, 10 and 14 days following cyclophosphamide administration (control, 215 +/- 24 7-day, 102 +/- 20 10-day, 59 +/- 4 and 14-day group, 76 +/- 8 nmol/mg/min). Cytochrome b5 content was significantly reduced (p < 0.0001) 7 and 10 days following cyclophosphamide administration (control, 0.46 +/- 0.13 7-day, 0.28 +/- 0.07 and 10-day group, 0.20 +/- 0.03 nmol/mg). 6. The significant reductions in the activity of rat hepatic microsomal 2D1 following cyclophosphamide administration, as seen by the alterations in mean Vmax for dextrorphan formation, do not appear to be due to a single factor, but may result from a combination of several events, including reductions in relative 2D1 content, reduced nicotinamide adenine dinucleotide phosphate P450-reductase activity and cytochrome b5 content.
Publisher: Oxford University Press (OUP)
Date: 04-1995
DOI: 10.1111/J.2042-7158.1995.TB05805.X
Abstract: A specific HPLC method with UV detection was used to investigate the disposition of morphine and its metabolites in the in-situ rat isolated perfused liver preparation. Livers of male Sprague-Dawley rats (n = 4) were perfused under single pass conditions with protein-and erythrocyte-free perfusate, containing 2·66 μm morphine, for up to 90 min. The concentration of morphine, normorphine and morphine-3-glucuronide (M3G) in outflow perfusate, and the biliary excretion of M3G and normorphine glucuronide, all reached steady-state levels within 15–20 min after commencing perfusion. At steady-state, the mean (± s.d.) extraction ratio of morphine was 0·87 ± 0·06 and clearance (26·0 ± 1·7 mL min−1) approached perfusate flow rate (30 mL min−1). Although M3G was the main metabolite, accounting for 72·8 ± 12·7% of eliminated morphine, a significant proportion (21·6 ± 13·5%) was N-demethylated to normorphine and was recovered as unchanged normorphine in outflow perfusate and normorphine glucuronide in bile. The biliary extraction ratio of hepatically-formed M3G was 0·61 ± 0·31. Results from an additional six experiments, in which livers were perfused with 1·33 and 2·66 μm of morphine for 30 min each in a balanced cross-over manner, indicated that the disposition of morphine and its metabolites was approximately linear within this concentration range.
Publisher: Oxford University Press (OUP)
Date: 05-1996
DOI: 10.1111/J.2042-7158.1996.TB05961.X
Abstract: The rat single-pass isolated perfused liver preparation was used to study the effects of altered perfusate flow rate on the hepatic disposition of morphine and its polar metabolite morphine-3-glucuronide (M3G). Using a balanced, cross-over design, livers of female Sprague-Dawley rats (n = 6) were perfused at 15 and 30 mL min−1 with erythrocyte- and protein-free perfusion medium containing a constant concentration of morphine (2.7 μM). After reaching steady-state, inflow and outflow perfusate and bile s les were collected and morphine and M3G were measured by HPLC. Doubling of perfusate flow rate was associated with a significant increase (P & 0.05) in the availability of morphine (mean ±s.d. of 0.19± 0.06 at 15 mL min−1 and 0.29 ± 0.08 at 30 mL min−1). The magnitude of the change in morphine availability was consistent with the predictions of the well-stirred model of hepatic elimination. The fate of hepatically generated M3G was assessed by the biliary extraction ratio of M3G alterations in perfusate flow rate had no significant effect on this ratio (mean ± s.d. of 0.49 ± 0.14 at a perfusate flow rate of 15 mL min−1 and 0.47 ± 0.22 at 30 mL min−1). A physiologically-based mathematical model, in which the vascular and intracellular spaces of the liver were represented by two well-mixed compartments, was utilized to derive an equation for the biliary extraction ratio of M3G. According to the model, the value of this extraction ratio will become insensitive to changes in perfusate flow rate when the permeability for M3G of the membrane separating the intracellular and vascular compartments is low compared with perfusate flow rate. Hence, the experimental results are consistent with the concept that the hepatic sinusoidal membrane represents a diffusional barrier to M3G.
Publisher: Oxford University Press (OUP)
Date: 03-2011
DOI: 10.1111/J.2042-7158.2010.01244.X
Abstract: This study was designed to investigate the renal disposition of 4-methylumbelliferone (4MU) and 4-methylumbelliferyl glucuronide (4MUG) to characterise the contribution of excretion and metabolic clearance to total clearance in the kidney. The isolated perfused kidney (IPK) from the male Sprague–Dawley rat was used in filtering and non-filtering mode to study the renal disposition of 4MU, renally generated 4MUG and preformed 4MUG. Perfusate and urine (filtering IPK only) was collected for up to 120 min and 4MU and 4MUG in perfusate and urine were determined by HPLC. Analytes were also measured in kidney tissue collected at 120 min. Non-compartmental analysis was used to derive pharmacokinetic parameters. The concentration of 4MU in perfusate declined with a terminal half-life of approximately 120 min following administration to the filtering IPK and nonfiltering IPK. There was a corresponding increase in the concentration of 4MUG. Metabolic clearance of 4MU accounted for 92% of total renal clearance. After bolus dosing of preformed 4MUG in the perfusion reservoir of the filtering IPK, the perfusate concentration declined with the terminal half-life of approximately 260 min. The renal excretory clearance of preformed 4MUG accounted for 96% of total renal clearance. 4MU was extensively metabolized by glucuronidation in the filtering and nonfiltering IPK, and the total renal clearance of 4MU was far greater than its renal excretory clearance. This indicated that glucuronidation was the major elimination pathway for 4MU in the kidney. The data confirmed an important role for the kidney in the metabolic clearance of xenobiotics via glucuronidation and signalled the lack of impact of impaired glomerular filtration on renal drug metabolism.
Publisher: Elsevier BV
Date: 03-1996
Publisher: OMICS Publishing Group
Date: 2010
DOI: 10.4172/JBB.1000032
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 04-11-2006
Abstract: Mycophenolic acid (MPA) is part of the immunosuppressant therapy for transplant recipients. This study examines the role of the canalicular transporter, Mrp2, and the effect of cyclosporin A (CsA), on the biliary secretion of the ether (MPAGe) and acyl (MPAGa) glucuronides of MPA. Isolated livers from Wistar rats (n = 6), or Wistar TR- rats (n = 6) were perfused with MPA (5 mg/l). A third group of Wistar rats (n = 6) was perfused with MPA and CsA (250 microg/l). There was no difference in the half-life, hepatic extraction ratio (E(H)), clearance or partial clearance of MPA to MPAGe, but there was a difference in partial clearance to MPAGa between control and CsA groups (0.9 +/- 0.4 versus 0.5 +/- 0.1 ml/min). TR- rats had a lower E(H) (0.59 +/- 0.30 versus 0.95 +/- 0.30), a lower clearance (18 +/- 8 versus 29 +/- 7 ml/min), and a longer half-life (19.5 +/- 10.3 versus 10.1 +/- 2.4 min) than controls. Compared to controls, MPAGe and MPAGa biliary excretion was reduced by 99% and 71.8%, respectively, in TR- rats, and 17.5% and 53.8%, respectively, in the MPA-CsA group. The biliary excretion of MPAGe is mediated by Mrp2, whereas that of MPAGa seems to depend on both Mrp2 and another unidentified canalicular transporter. Although CsA can inhibit Mrp2, our data suggest that it may also inhibit the hepatic glucuronidation of MPA in Wistar rats.
Publisher: Wiley
Date: 2006
DOI: 10.1002/BMC.554
Abstract: Development, validation and application of an HPLC assay for new antiviral nucleoside analogues AM365 and AM188 in isolated perfused rat liver perfusate and bile were performed. An analytical column (Phenosphere-NEXT, 250 x 4.6 mm, C(18), 4 microm, Phenomenex) was used in tandem with a guard column (4 x 3 mm, C(18), Phenomenex) and operated at 25 degrees C. The mobile phase [methanol:10 mmol/L sodium orthophosphate buffer (pH 7.0), 15:85, v/v] was pumped at 1 mL/min. The signal from a diode array detector was collected from 190 to 300 nm. The chromatogram was processed at 220 and 252 nm for AM365 and AM188, respectively. The HPLC method was validated by six intraday and seven interday runs. Standard curves were linear in the range 0.125-8.00 microg/mL for AM365 and AM188, and the lower limit of quantification for AM365 and AM188 was 0.125 microg/mL. Mean interday precision and accuracy of IPL perfusate quality control s les were within 8.8%, and mean intraday precision and accuracy were within 13.1%. The assay has been successfully used in the study of metabolism and disposition of AM365 in the isolated perfused rat liver.
Publisher: Elsevier BV
Date: 11-2004
Publisher: Crossref
Date: 10-07-2007
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 10-06-2005
Abstract: Hepatic uptake of propionyl-L-carnitine (PLC) and L-carnitine (LC) was assessed with the impulse-response technique in the single-pass perfused rat liver. The experiments involved a rapid injection (impulse) of a mixture of the radiolabeled test compound (PLC or LC) and a reference compound (sucrose) into portal vein inflow and collection and radiochemical analysis (response) of the venous outflowing perfusate s les. The impulse injection was made in the presence of increasing unlabeled background concentrations of PLC (0-50 microM) or LC (50-500 microM) perfusing the liver. The hepatic uptake was minimal or negligible for LC, whereas the hepatic influx clearance was found to be low (0.095 ml/s equivalent to 5.7 ml/min) for PLC relative to the perfusate flow rate (30 ml/min). When background concentrations of PLC were increased (from 1-50 microM), the influx clearance was reduced in a concentration-dependent behavior, indicating partial saturation of the entry of compound into hepatocytes. PLC was taken up into hepatocytes via a unidirectional transport process with negligible efflux. The hepatic uptake of PLC was significantly reduced in the presence of unlabeled LC (500 microM), indicating an inhibition of the sinusoidal membrane transport of PLC by LC. The study showed the sinusoidal membrane is a permeability barrier to the entry of PLC and LC into hepatocytes, and it is the site of a common carrier-mediated transporter for both compounds.
Publisher: Elsevier BV
Date: 04-2003
DOI: 10.1016/S0272-6386(03)00113-6
Abstract: Among the homeostatic processes controlling the endogenous L-carnitine pool in humans, the kidney has a vital role through extensive and adaptive tubular reabsorption. Kidney disease can lead to disturbances in L-carnitine homeostasis, and long-term hemodialysis therapy can lead to a significant reduction in plasma and tissue L-carnitine levels and an increase in the ratio of acyl-L-carnitine to free L-carnitine. These alterations may interfere with the oxidation of fatty acids and removal from tissues of unwanted short-chain acyl groups. A dialysis-related carnitine disorder (DCD) arises when these biochemical abnormalities exist in association with such clinical symptoms as muscle weakness, cardiomyopathy, intradialytic hypotension, or anemia that is resistant to erythropoietin therapy. Exogenous L-carnitine, administered intravenously, is approved for the treatment of secondary carnitine deficiency caused by long-term hemodialysis. Although intravenous administration of 20-mg/kg doses at the end of each hemodialysis session leads to supraphysiological levels of the compound in plasma, these levels do not appear to be associated with adverse effects. Because more than 99% of the body's carnitine pool is located outside of plasma, supraphysiological plasma levels appear to be required to ensure that depleted muscle stores can be replenished. Although oral L-carnitine has been used for the treatment of DCD, the bioavailability of oral L-carnitine is low (<15%) in healthy subjects and unknown in patients with end-stage renal disease. Moreover, gastrointestinal degradation of L-carnitine to trimethylamine and other compounds might limit the usefulness of long-term oral L-carnitine administration in this patient group.
Publisher: Wiley
Date: 09-1990
DOI: 10.1111/J.1476-5381.1990.TB12097.X
Abstract: 1. Intracellular recordings have been made of the hyperpolarization of cockroach salivary gland cells induced by nerve stimulation and dopamine. 2. The relative potency of a number of dopamine antagonists in inhibiting the dopamine- and nerve-mediated hyperpolarization was studied. SCH23390 (10-50 microM), chlorpromazine (0.1-5 microM), haloperidol (10-100 microM) and metoclopramide (1 mM) inhibited the hyperpolarization. 3. In contrast, domperidone and (+/-)-sulpiride potentiated the hyperpolarization induced by both nerve stimulation and dopamine. 4. Apparent dissociation constants (KDapp) were obtained for the blockade of the dopamine-induced hyperpolarization. The rank order of potency (KDapp in parentheses) was as follows: chlorpromazine (0.2 microM) haloperidol (3.3 microM) SCH23390 (4.1 microM) metoclopramide (265 microM) domperidone and (+/-)-sulpiride (inactive). 5. It is concluded that the receptor subserving the dopamine-induced hyperpolarization of the salivary gland acinar cells is the same as that mediating the secretory response to dopamine. In addition these data support our findings, which suggested that this receptor is similar to the D1 dopamine receptor, but distinct from the D2 receptor found in mammalian systems.
Publisher: Springer Science and Business Media LLC
Date: 2003
DOI: 10.2165/00003088-200342110-00002
Abstract: L-Carnitine is a naturally occurring compound that facilitates the transport of fatty acids into mitochondria for beta-oxidation. Exogenous L-carnitine is used clinically for the treatment of carnitine deficiency disorders and a range of other conditions. In humans, the endogenous carnitine pool, which comprises free L-carnitine and a range of short-, medium- and long-chain esters, is maintained by absorption of L-carnitine from dietary sources, biosynthesis within the body and extensive renal tubular reabsorption from glomerular filtrate. In addition, carrier-mediated transport ensures high tissue-to-plasma concentration ratios in tissues that depend critically on fatty acid oxidation. The absorption of L-carnitine after oral administration occurs partly via carrier-mediated transport and partly by passive diffusion. After oral doses of 1-6g, the absolute bioavailability is 5-18%. In contrast, the bioavailability of dietary L-carnitine may be as high as 75%. Therefore, pharmacological or supplemental doses of L-carnitine are absorbed less efficiently than the relatively smaller amounts present within a normal diet.L-Carnitine and its short-chain esters do not bind to plasma proteins and, although blood cells contain L-carnitine, the rate of distribution between erythrocytes and plasma is extremely slow in whole blood. After intravenous administration, the initial distribution volume of L-carnitine is typically about 0.2-0.3 L/kg, which corresponds to extracellular fluid volume. There are at least three distinct pharmacokinetic compartments for L-carnitine, with the slowest equilibrating pool comprising skeletal and cardiac muscle.L-Carnitine is eliminated from the body mainly via urinary excretion. Under baseline conditions, the renal clearance of L-carnitine (1-3 mL/min) is substantially less than glomerular filtration rate (GFR), indicating extensive (98-99%) tubular reabsorption. The threshold concentration for tubular reabsorption (above which the fractional reabsorption begins to decline) is about 40-60 micromol/L, which is similar to the endogenous plasma L-carnitine level. Therefore, the renal clearance of L-carnitine increases after exogenous administration, approaching GFR after high intravenous doses. Patients with primary carnitine deficiency display alterations in the renal handling of L-carnitine and/or the transport of the compound into muscle tissue. Similarly, many forms of secondary carnitine deficiency, including some drug-induced disorders, arise from impaired renal tubular reabsorption. Patients with end-stage renal disease undergoing dialysis can develop a secondary carnitine deficiency due to the unrestricted loss of L-carnitine through the dialyser, and L-carnitine has been used for treatment of some patients during long-term haemodialysis. Recent studies have started to shed light on the pharmacokinetics of L-carnitine when used in haemodialysis patients.
Publisher: Wiley
Date: 12-07-2008
DOI: 10.1111/J.1440-1797.2007.00817.X
Abstract: It has been widely established that patients with end-stage renal disease undergoing chronic haemodialysis therapy exhibit low endogenous levels of L-carnitine and elevated acylcarnitine levels however, the clinical implication of this altered carnitine profile is not as clear. It has been suggested that these disturbances in carnitine homeostasis may be associated with a number of clinical problems common in this patient population, including erythropoietin-resistant anaemia, cardiac dysfunction, and dialytic complications such as hypotension, cr s and fatigue. In January 2003, the Centers for Medicare and Medicaid Services (USA) implemented coverage of intravenous L-carnitine for the treatment of erythropoietin-resistant anaemia and/or intradialytic hypotension in patients with low endogenous L-carnitine concentrations. It has been estimated that in the period of 1998-2003, 3.8-7.2% of all haemodialysis patients in the USA received at least one dose of L-carnitine, with 2.7-5.2% of patients receiving at least 3 months of supplementation for one or both of these conditions. The use of L-carnitine within Australia is virtually non-existent, which leads us to the question: Are Australian haemodialysis patients missing out? This review examines the previous research associated with L-carnitine administration to chronic dialysis patients for the treatment of anaemia, cardiac dysfunction, dyslipidaemia and/or dialytic symptoms, and discusses whether supplementation is warranted within the Australian setting.
Publisher: Springer Science and Business Media LLC
Date: 03-0009
DOI: 10.1007/BF00266343
Abstract: T cell colonies were generated from the peripheral blood and bone marrow of 11 patients with acquired immune deficiency syndrome (AIDS), 17 normal male and female heterosexuals and seven clinically normal male homosexuals. Mononuclear cells were cultured in methylcellulose both in the absence and presence of interleukin-2 (IL-2) containing conditioned medium. Clinically normal homosexuals showed a low number of T4+ (P less than 0.01) but not T8+ cells. The number of T cell colony forming cells (T-CFC) from both AIDS patients and homosexuals was significantly (P less than 0.01) reduced compared to T-CFC from normal heterosexuals. In seven and four out of 11 AIDS patients, T-CFC from peripheral blood and bone marrow, respectively, were able to generate colonies in the absence of added growth factors and/or mitogenic stimulation. Pooled spontaneous and induced colonies from AIDS patients as well as induced colonies from normal homosexuals were composed of immature cells bearing the T3+, T4+, T6+ T8+ surface phenotype, unlike colonies from normal heterosexuals which displayed mature cells bearing the T3+ T4+ T6- and T3+ T8+ T6- surface phenotype. Moreover, most T-CFC from primary spontaneous and induced colonies had lost their self-renewal capacity either in the absence or the presence of added growth factors. These results suggest that early impairment of T-CFC may play a predominant role in the pathogenesis of AIDS.
Publisher: Oxford University Press (OUP)
Date: 05-2003
DOI: 10.1211/002235703765344540
Abstract: This study examines the potential for the phytoestrogenic isoflavones, a type of complementary medicine, to be involved in pharmacokinetic interactions in the liver. Rat livers were isolated and perfused to steady state, in single-pass mode, with either 5 μm paracetamol (n=6), or 5 μm paracetamol with a 50:50 molar mixture of genistein and biochanin A or daidzein and formononetin, at a total isoflavone concentration of 1 and 10 μm (n = 6 for each mixture at each concentration). At 1 μm, neither isoflavone mixture had any effect, while at 10 μm both mixtures decreased the clearance of paracetamol and the formation clearance to paracetamol sulfate. Genistein and biochanin A (10 μm) also increased the biliary extraction of hepatically-generated paracetamol sulfate. Additional livers were perfused with an infusion of 5 μm 14C-paracetamol in the absence (n = 4), or presence, of a 10 μm genistein and biochanin A mixture (n = 4). Analysis of washout perfusate and bile s les (up to 30min after stopping the infusion) revealed that the isoflavones reduced the first-order rate constant for paracetamol sulfate transport into perfusate, but not for transport into bile. The results indicate that isoflavones can reduce the formation of paracetamol sulfate and that its enhanced excretion into bile arises from the inhibition of sinusoidal efflux transport.
Publisher: SAGE Publications
Date: 09-2005
Abstract: Background: Patients with end-stage renal disease (ESRD) undergoing long-term haemodialysis exhibit low L-carnitine and elevated acylcarnitine concentrations. This study evaluated endogenous concentrations of an array of acylcarnitines (carbon chain length up to 18) in healthy in iduals and ESRD patients receiving haemodialysis, and examined the impact of a single haemodialysis session on acylcarnitine concentrations. Methods: Blood s les were collected from 60 healthy subjects and 50 ESRD patients undergoing haemodialysis (pre- and post-dialysis s les). Plasma s les were analysed for in idual acylcarnitine concentrations by electrospray MS/MS. Results: Of the 31 acylcarnitines, 29 were significantly ( P .05) elevated in ESRD patients compared with healthy controls in particular, C5 and C8:1 concentrations were substantially elevated. For acylcarnitines with a carbon chain length less than eight, plasma acylcarnitine concentrations decreased significantly over the course of a single dialysis session however, post-dialysis concentrations invariably remained significantly higher than those in healthy subjects. Dialytic removal of acylcarnitines diminished once the acyl chain length exceeded eight carbons. Conclusions: The accumulation of acylcarnitines during long-term haemodialysis suggests that removal by haemodialysis is less efficient than removal from the body by the healthy kidney. Removal is significantly correlated to acyl chain length, most likely due to the increased molecular weight and lipophilicity that accompanies increased chain length.
Publisher: Springer Science and Business Media LLC
Date: 02-1990
DOI: 10.2165/00003088-199018020-00004
Abstract: Phorbol myristate acetate (pma) is a potent mitogen for human peripheral blood lymphocytes (PBL) comparable to phytohemagglutinin (PHA) in potency. Inactivation of PHA-responsive lymphocytes by 5'-bromodeoxyuridine and light treatment left the PMA response intact and nice versa. Experiments separating lymphocytes by rosetting with sheep erythrocytes (SRBC) demonstrated that the PMA-responsive lymphocytes segregate with those that have a high affinity for SRBC to a greater than PHA- or concanavalin A (Con A)-responsive cells. These results indicate that a PMA-responsive population in human peripheral blood resides within the T-lymphocyte population and appears to have a high affinity for SRBC and to be distinct from that responding to PHA and Con A. PMA may be useful clinically to assay the size and function of the high affinity or "active" rosette population.
Publisher: Oxford University Press (OUP)
Date: 16-11-2019
DOI: 10.1093/JAC/DKY466
Abstract: Ribavirin is used in the treatment of respiratory paramyxovirus infection in lung transplant recipients however, its pharmacokinetic profile in the transplant population is unknown despite the potential for alterations due to underlying pathology. Furthermore, the ability of current regimens to meet exposure targets has not been established. This study examined the pharmacokinetics of ribavirin in a lung transplant population for which current and alternative dosing regimens were assessed. Population pharmacokinetic modelling was conducted in NONMEM using concentration-time data from 24 lung transplant recipients and 6 healthy volunteers. Monte Carlo simulation was used to assess the ability of dosing regimens to achieve pre-specified target concentrations. A three-compartment model with first-order elimination most adequately described ribavirin concentration-time data, with CLCR and patient type (i.e. lung transplant) identified as significant covariates in the model. Simulations indicate that current regimens achieve efficacious concentrations within 24 h of treatment initiation that increase to supra-therapeutic levels over the treatment period. A regimen of 8 mg/kg q6h orally for 48 h followed by 8 mg/kg q24h orally for the remainder of the treatment period was predicted to result in >90% of patients exhibiting concentrations within the defined target range throughout the entire treatment course. Additional work to formally establish target therapeutic concentrations is required however, this study provides a valuable first step in determining optimal ribavirin treatment regimens for paramyxovirus infections in the lung transplant population.
Publisher: Springer Science and Business Media LLC
Date: 1990
DOI: 10.2165/00003088-199018010-00003
Abstract: Phenytoin, which is used primarily as an anticonvulsant agent, has a relatively low therapeutic index, and monitoring of plasma phenytoin concentration is often used to help guide therapy. It has properties which predispose it to an involvement in pharmacokinetic interactions, a large number of which have been reported. These properties include: low aqueous solubility and slow rate of gastrointestinal absorption a relatively high degree of plasma protein binding a clearance that is non-linear due to saturable oxidative biotransformation and the ability to induce hepatic microsomal enzymes. Because of its narrow therapeutic range, drug interactions leading to alterations in plasma phenytoin concentration may be clinically important. Such interactions have often been reported initially as either cases of phenytoin intoxication or of decreased effectiveness. Drugs may modify the pharmacokinetics of phenytoin by altering its absorption, plasma protein binding, or hepatic biotransformation alterations in the absorption and/or biotransformation may lead to changes in both the unbound plasma phenytoin concentration and, as a result, the clinical effect. Preparations which may decrease the gastrointestinal absorption of phenytoin include nutritional formulae and charcoal. There are many reports of drugs which may increase (e.g. folic acid, dexamethasone and rif icin) or decrease (e.g. valproic acid, sulthiame, isoniazid, cimetidine, phenylbutazone, chlor henicol and some sulphonamides) the metabolism of phenytoin. It is important to bear in mind that, as a result of its non-linear clearance, changes in phenytoin absorption and/or biotransformation will lead to more than proportionate changes in plasma drug concentration. Drugs which may displace phenytoin from plasma albumin include valproic acid, salicylic acid, phenylbutazone and some sulphonamides. Although an alteration in the unbound fraction of phenytoin in plasma would not, in itself, be expected to alter the unbound plasma phenytoin concentration, the interpretation of total plasma concentrations for therapeutic drug monitoring may be confounded. Some drugs appear to alter phenytoin pharmacokinetics via dual mechanisms (e.g. valproic acid and phenylbutazone), while for other compounds the mechanism of interaction has not been fully elucidated. Phenytoin has been reported to alter the pharmacokinetics of a large number of drugs. The majority of these interactions arise because phenytoin is a potent inducer of cytochrome P450 microsomal enzymes, and therefore may increase the clearance of drugs which are extensively metabolised drugs affected include carbamazepine, theophylline, methadone, prednisolone, dexamethasone, metyrapone and several cardiac antiarrhythmic agents. With all of these, the resultant decrease in plasma concentrations may be clinically important.(ABSTRACT TRUNCATED AT 400 WORDS)
Publisher: Oxford University Press (OUP)
Date: 10-2003
Abstract: Foods and complementary medicines contain phytoestrogenic isoflavones such as genistein, which undergo hepatic glucuronidation and excretion into bile and can potentially interfere with the hepatic elimination of other compounds. To investigate this potential, livers from Sprague-Dawley rats were perfused in single-pass mode with preformed gemfibrozil 1-O-acyl glucuronide (GG) (1 μM, n = 12) for 60 min followed by a 30-min washout phase, or with gemfibrozil (1 μM n = 10) for 120 min. Half of each group of livers were co-perfused with genistein (10 μM) throughout the experiment. Perfusate and bile were analyzed for GG and gemfibrozil by HPLC. Co-perfusion with genistein significantly (P & 0.05) decreased the biliary extraction ratio of preformed GG from a mean of 0.82 to 0.65 and the first-order rate constant for transport of GG into bile from 0.054 + 0.010 to 0.032 + 0.008 min−1, but increased the first-order rate constant for sinusoidal efflux of GG from 0.128 + 0.023 to 0.227 + 0.078 min−1. Co-perfusion with genistein also significantly decreased the biliary extraction ratio of hepatically generated GG from 0.95 + 0.01 to 0.83 + 0.05. The findings confirm that genistein increases the potential for hepatic and systemic exposure to hepatically generated glucuronides, which may be important for patients on conventional drugs who consume isoflavones.
Publisher: Wiley
Date: 2001
DOI: 10.1046/J.1440-1681.2001.03393.X
Abstract: 1. Pseudoephedrine is a weak organic base that undergoes renal tubular secretion. The aim of the present study was to assess whether two other commonly used weak organic bases (cimetidine and morphine) inhibit the renal tubular secretion of pseudoephedrine in the rat isolated perfused kidney. 2. A total of 12 perfusions were performed with four perfusions in each of three treatment groups. In the control group, pseudoephedrine was administered as a bolus dose of [ 14 C]‐pseudoephedrine and unlabelled pseudoephedrine to achieve an initial perfusate concentration of 0.4 μg/mL. For the treatment groups, pseudoephedrine was administered as above and cimetidine or morphine was added to the perfusion medium in increasing concentrations of 0.5–12.5 and 0.2–5.0 μg/mL, respectively. 3. The mean (±SD) fraction unbound of pseudoephedrine alone in perfusate was 0.866±0.014 and was not different ( P 0.05) in the presence of cimetidine or morphine. 4. In control experiments, the renal excretory clearance (CL R ) of pseudoephedrine was three‐fold greater than glomerular filtration rate (GFR), yielding a ratio consistently greater than unity, which indicates extensive net tubular secretion of pseudoephedrine. The CL R and total clearance of pseudoephedrine were similar, suggesting an absence of renal metabolism of pseudoephedrine. 5. The CL R /GFR ratio for pseudoephedrine was not affected by morphine, but was significantly reduced ( P 0.05) in the presence of cimetidine. 6. The results indicate that cimetidine inhibits the renal tubular secretion of pseudoephedrine.
Publisher: Springer Science and Business Media LLC
Date: 09-2000
Abstract: L-Carnitine is an endogenous molecule involved in fatty acid metabolism. Secondary carnitine deficiency may develop in patients with end-stage renal disease undergoing long-term hemodialysis because of dialytic loss. In these patients L-carnitine can be administered to restore plasma and tissue levels. The objective of this study was to evaluate the pharmacokinetics of intravenous L-carnitine in patients undergoing long-term hemodialysis. Twelve patients undergoing three dialysis sessions/week received L-carnitine intravenously (20 mg x kg(-1)) at the end of each dialysis session for 9 weeks. Plasma s les were analyzed for L-carnitine, acetyl-L-carnitine, and total carnitine by HPLC. Under baseline conditions, the mean +/- SD predialysis plasma concentration of L-carnitine was 19.5 +/- 5.6 micromol/L, decreasing to 5.6 +/- 1.9 micromol/L at the end of the dialysis session. These concentrations were substantially lower than endogenous levels in healthy human beings. Under baseline conditions the extraction ratios of L-carnitine and acetyl-L-carnitine by the dialyser were 0.74 +/- 0.07 and 0.71 +/- 0.11, respectively. During repeated dosing, there was accumulation of L-carnitine in plasma, and after 9 weeks of dosing, the predialysis and postdialysis plasma levels were 191 +/- 54.1 and 41.8 +/- 13.0 micromol/L, respectively. The predialysis and postdialysis plasma levels of L-carnitine decreased once dosing was ceased but had not returned to pretreatment levels after 6 weeks. The study demonstrated that removal of L-carnitine by hemodialysis is extremely efficient and that patients undergoing hemodialysis had plasma concentrations that were substantially lower than normal, particularly during dialysis. During repeated administration of L-carnitine, the predialysis and postdialysis concentrations of the compound increased steadily, reaching an apparent steady state after about 8 weeks. It is proposed that this accumulation arose from the distribution of L-carnitine into a deep tissue pool that includes skeletal muscle.
Publisher: Wiley
Date: 10-2006
Abstract: The pharmacokinetics of L-carnitine and its metabolites were investigated in 7 healthy subjects following the oral administration of 0, 0.5, 1, and 2 g 3 times a day for 7 days. Mean plasma concentrations of L-carnitine across an 8-hour dose interval increased significantly (P < .05) from a baseline of 54.2 +/- 9.3 microM to 80.5 +/- 12.5 microM following the 0.5-g dose there was no further increase at higher doses. There was a significant increase (P < .001) in the renal clearance of L-carnitine indicating saturation of tubular reabsorption. Trimethylamine plasma levels increased proportionately with L-carnitine dose, but there was no change in renal clearance. A significant increase in the plasma concentrations of trimethylamine-N-oxide from baseline was evident only for the 2-g dose of L-carnitine (from 34.5 +/- 2.0 to 149 +/- 145 microM), and its renal clearance decreased with increasing dose (P < .05). There was no evidence for nonlinearity in the metabolism of trimethylamine to trimethylamine-N-oxide. In conclusion, the pharmacokinetics of oral L-carnitine display nonlinearity above a dose of 0.5 g 3 times a day.
Publisher: Elsevier BV
Date: 07-2005
DOI: 10.1016/J.JPBA.2005.01.040
Abstract: The aim of this study was to evaluate the usefulness of IAM chromatography in building a model that would allow prediction of drug absorption in humans. The human intestinal absorption values (%HIA) for 52 drugs with low to high intestinal absorption were collected from the literature. The retention (capacity factor, k') of each drug was measured by reverse-phase HPLC using an IAM.PC.DD2 column (prepared with phosphatidylcholine analogs, 12 microM, 300A, 15 cm x 4.6 mm) with an eluent of acetonitrile-0.1M phosphate buffer at pH 5.4. In addition, 76 molecular descriptors and solubility parameters for each drug were calculated using ChemSW from the 3D-molecular structures. Stepwise regression was employed to develop a regression equation that would correlate %HIA with molecular descriptors and k'. Human intestinal absorption was reciprocally correlated to the negative value of the capacity factor (-1/k') (R=0.64). The correlation was further improved with the addition of molecular descriptors representing molecular size and shape (molecular width, length and depth) solubility (solubility parameter, HLB, hydrophilic surface area) and polarity (dipole, polar surface area) (R=0.83). Experimentally measured IAM chromatography retention values and calculated molecular descriptors and solubility parameters can be used to predict intestinal absorption of drugs in humans. Developed QSAR can be used as a screening method in the designing of drugs with appropriate IA and for the selection of drug candidates in the early stage of drug discovery process.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 06-05-2011
Abstract: In this study, the selectivity of UDP-glucuronosyltransferase (UGT) enzyme inhibition by ketamine (KTM) and the kinetics of KTM inhibition of human liver microsomal morphine (MOR) and codeine (COD) glucuronidation were characterized to explore a pharmacokinetic basis for the KTM-opioid interaction. With the exception of UGT1A4, KTM inhibited the activities of recombinant human UGT enzymes in a concentration-dependent manner. However, IC(50) values were 50% increases in the in vivo area under the curve ratios) with MOR and COD were predicted for anesthetic doses of KTM and for a subanesthetic dose of KTM on COD glucuronidation.
Publisher: Wiley
Date: 02-1997
DOI: 10.1111/J.1440-1681.1997.TB01797.X
Abstract: 1. The effect of albumin on the disposition of morphine and hepatically generated morphine-3-glucuronide (M3G) was investigated in the single-pass rat isolated perfused liver. 2. Using a balanced cross-over design, each of 10 livers was perfused at 30 mL/min with medium containing 2.7 mumol/L morphine in the presence and absence of 10 g/L bovine serum albumin (BSA). 3. Both bile flow rate and hepatic oxygen consumption were significantly higher (P 0.05) by the presence or absence of BSA. 6. The fraction of morphine escaping heptic extraction in the absence of BSA (mean +/- SD 0.41 +/- 0.14) was not altered significantly (P > 0.05) by the presence of the protein in perfusate (0.35 +/- 0.13), indicating no change in the intrinsic clearance or morphine despite the difference in oxygen consumption. 7. The fraction of hepatically generated M3G excreted in bile was significantly higher (P < 0.005) when BSA was present in the perfusate than when it was not (0.44 +/- 0.14 vs 0.38 +/- 0.16, respectively). 8. The results are consistent with the concept that BSA modifies the ability of solutes, including M3G, to move through the paracellular pathway from the canalicular to the vascular space. 9. It is concluded that because albumin may modify not only the unbound fraction of a ligand in perfusate, but also the functional performance of the liver, care is needed in the interpretation of studies examining the influence of the protein on the hepatic disposition of drugs and their metabolites.
Publisher: Wiley
Date: 05-12-2019
DOI: 10.1002/PSP4.12364
Publisher: Wiley
Date: 08-2000
Publisher: Springer Science and Business Media LLC
Date: 1997
Abstract: Humans and guinea pigs metabolise morphine extensively, forming the isomers morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in relatively similar ratios. Both metabolites are formed in the liver, and their greater polarity relative to the parent aglycone may limit their permeability across hepatic membranes. This study compared the disposition of hepatically-generated M3G and M6G in perfused livers isolated from guinea pigs. Livers were perfused at 30 ml/min in a non-recirculating manner with Krebs bicarbonate buffer containing morphine (6 to 7 microM). Perfusing medium, venous perfusate and bile were collected at regular intervals and concentrations of morphine, M3G and M6G determined by reversed-phase HPLC. Concentrations of morphine, M3G and M6G in perfusate and the rates of biliary excretion of M3G and M6G were consistent between 20 and 50 min of perfusion. The mean (+/-s.d.) ratio for the rate of formation of M3G relative to M6G was 3.7 +/- 1.5. A mean 33 +/- 3% of morphine extracted by the liver was recovered as summed M3G and M6G. Of the M3G and M6G formed during a single passage, 19 +/- 11% and 9 +/- 9%, respectively, was excreted into bile the values were significantly different (P = 0.002). A greater fraction of hepatically-generated M3G excreted into bile compared to that for M6G reflects differences in their relative transport across sinusoidal and canalicular membranes of hepatocytes, possibly via carrier-mediated systems.
Publisher: Wiley
Date: 1998
DOI: 10.1111/J.1440-1681.1998.TB02140.X
Abstract: 1. The rat isolated perfused kidney (IPK) was used to determine whether the renal tubular secretion of ranitidine is influenced by clinically relevant concentrations of other organic cationic drugs (amantadine, pseudoephedrine, triamterene and trimethoprim) that also undergo tubular secretion. 2. Ranitidine and [3H]-ranitidine were administered to the recirculating perfusion medium as a loading dose followed by a constant infusion to maintain clinically relevant perfusate ranitidine concentrations in the range 400-700 ng/mL. The renal clearance of ranitidine (CL[R]) was calculated, as was glomerular filtration rate (GFR), from the renal clearance of [14C]-inulin. 3. A total of 20 perfusions were performed and, in each case, ranitidine was administered for 80 min. In four control IPK, no drug other than ranitidine was administered. In the remaining IPK, amantadine, pseudoephedrine, triamterene or trimethoprim (n = 4 in each case) were administered to achieve low, medium and high concentrations during the 20-40, 40-60 and 60-80 min periods, respectively. 4. The mean (+/- SD) unbound fraction of ranitidine in the perfusion medium was 0.889 +/- 0.046 and was not altered (P>0.05) by the presence of the other drugs. 5. The CL(R)/GFR ratio for ranitidine in all kidneys was substantially greater than unity and had a mean value of 10.65 or greater in control kidneys, indicating extensive net tubular secretion. 6. The CL(R)/GFR was not affected (P>0.05) by amantadine, pseudoephedrine or triamterene at any concentration or by trimethoprim at the low concentration. However, medium (2000 ng/mL) and high (5000 ng/mL) concentrations of trimethoprim caused significant reductions in CL(R)/GFR of 20 and 28%, respectively (P<0.05). 7. The results indicate that at clinically relevant concentrations the renal tubular secretion of ranitidine is inhibited by trimethoprim, but not by amantadine, pseudoephedrine or triamterene.
Publisher: Springer Science and Business Media LLC
Date: 04-1992
DOI: 10.1007/BF01071000
Publisher: Wiley
Date: 19-01-2011
DOI: 10.1111/J.1365-2796.2010.02341.X
Abstract: The underlying aetiology of chronic fatigue syndrome is currently unknown however, in the light of carnitine's critical role in mitochondrial energy production, it has been suggested that chronic fatigue syndrome may be associated with altered carnitine homeostasis. This study was conducted to comparatively examine full endogenous carnitine profiles in patients with chronic fatigue syndrome and healthy controls. A cross-sectional, observational study. Forty-four patients with chronic fatigue syndrome and 49 age- and gender-matched healthy controls were recruited from the community and studied at the School of Pharmacy & Medical Sciences, University of South Australia. All participants completed a fatigue severity scale questionnaire and had a single fasting blood s le collected which was analysed for l-carnitine and 35 in idual acylcarnitine concentrations in plasma by LC-MS/MS. Patients with chronic fatigue syndrome exhibited significantly altered concentrations of C8:1, C12DC, C14, C16:1, C18, C18:1, C18:2 and C18:1-OH acylcarnitines of particular note, oleyl-L-carnitine (C18:1) and linoleyl-L-carnitine (C18:2) were, on average, 30-40% lower in patients than controls (P < 0.0001). Significant correlations between acylcarnitine concentrations and clinical symptomology were also demonstrated. It is proposed that this disturbance in carnitine homeostasis is reflective of a reduction in carnitine palmitoyltransferase-I (CPT-I) activity, possibly a result of the accumulation of omega-6 fatty acids previously observed in this patient population. It is hypothesized that the administration of omega-3 fatty acids in combination with l-carnitine would increase CPT-I activity and improve chronic fatigue syndrome symptomology.
Publisher: Wiley
Date: 11-1996
DOI: 10.1111/J.1440-1681.1996.TB01151.X
Abstract: 1. The liver is ideally suited for the efficient uptake of drugs from sinusoidal blood. For most drugs, uptake into hepatocytes across the basolateral membrane occurs via passive diffusion, with minimal relaiance on carrier‐mediated transport systems. Often, this passive diffusion is so efficient that uptake is ratelimited by the delivery of the drug to the lvier (i.e. blood flow) rather than membrane transport per se 2. For highly polar molecules, passive diffusion no longer represents an efficient mode of hepatocellular uptake and there is an increased reliance on carrier‐mediated transport systems. For these compounds, membrane transport may dictate the overall efficiency of hepatic elimination. 3. Drug metabolites, particularly conjugated metabolites, such as sulphates and glucuronides, are invariably more polar than their precursors and are more likely to experience hepatocyte membranes as diffusional barriers. In the presence of such a barrier, the hepatocellular disposal of a locally formed metabolite will depend critically on the presence and activity of carrier‐mediated transport systems for sinusoidal efflux and biliary excretion. Transporters of current interest include P ‐glycoproteins, which are responsible for the biliary excretion of a rage of organic cations, and the canalicular multispecific organic anion transporter. 4. Intracellular trapping of hepatically formed metabolites, secondary to low membrane permeability, is clinically important as many metabolites are potentially hepatotoxic and/or capable of interfering with the hepatic transport of endogenous compounds or other durgs and metabolites. In addition, if the metabolite is unstable, intracellular accumulation can lead to the regeneration of the precursor and ‘futile cycling’ within hepatocytes. 5. An increased understanding of the factors influencing the intracellular concentrations of drugs and hepatically formed metabolites in the lvier will improve our ability to specifically treat liver disorders, such as hepatocellular carcinoma and malaria, and minimize the risk of hepatotoxicity from drugs and other xenobiotics.
Publisher: Springer Science and Business Media LLC
Date: 02-2004
DOI: 10.1023/B:JOPA.0000029486.60317.25
Abstract: Numerous studies have previously been conducted with the impulse-response isolated perfused rat liver (IR-IPRL) to establish the role of both physiological and physicochemical factors in determining solutes' pattern of hepatic disposition, however the impact of optical isomerism on hepatic disposition has hardly been studied using this methodology. In this study, the IR-IPRL was used to assess the extent of stereoselectivity exhibited by the kinetic processes involved in the hepatic disposition of the diastereomeric acyl glucuronides of (R)- and (S)-2-phenylpropionic acid (i.e. (R)- and (S)-PPAG). Moment and model-dependent (distributed model and axial dispersion model) analyses were conducted of the hepatic outflow profiles generated upon bolus administration of (R)-(14)C-PPAG or (S)-(14)C-PPAG and 3H-Sucrose (used as a marker of the hepatic vascular space) into the portal inflow of isolated perfused livers of male Sprague-Dawley rats (n = 4). Significant differences between (R)- and (S)-PPAG were apparent in the pharmacokinetic parameters defining the total hepatic disposition of the two diastereomers, the most marked being the hepatic availabilities, where the value for (S)-PPAG (0.721 +/- 0.059) was significantly lower than that of (R)-PPAG (0.909 +/- 0.042). The distributed and axial dispersion model analyses suggested that the more extensive hepatic extraction of (S)-PPAG was (at least in part) due to the higher sinusoidal membrane permeability-surface area product (PS UPT) of the diastereomer, and this has been considered in light of the emerging evidence regarding the role of hepatocellular membrane transport mechanisms. Furthermore, given the potential immunogenicity of acyl glucuronides (through covalent binding to plasma and intracellular proteins), the results of this study suggest that diastereomeric glucuronides may exhibit differing toxicity due to differences in their access to intracellular proteins.
Publisher: Wiley
Date: 03-1999
DOI: 10.1002/(SICI)1098-2299(199903/04)46:3/4<292::AID-DDR15>3.0.CO;2-4
Publisher: Springer Science and Business Media LLC
Date: 11-2001
DOI: 10.1007/BF03342662
Publisher: Elsevier BV
Date: 10-2004
Publisher: Wiley
Date: 2004
DOI: 10.1111/J.1440-1681.2004.03946.X
Abstract: 1. AM 188 is an antiviral guanosine analogue that undergoes extensive renal excretion in humans. The present study was designed to investigate the disposition of AM 188 over a range of concentrations in the rat isolated perfused kidney (IPK) to explore the mechanisms involved in its renal handling. 2. Right kidneys of male Sprague-Dawley rats (n = 23) were isolated and perfused in recirculating mode with Krebs'-Henseleit (pH 7.4) buffer containing 0.65% bovine serum albumin, 3.6% dextran, amino acids and glucose. [14C]-Inulin was added to the perfusate reservoir to permit estimation of glomerular filtration rate (GFR). [3H]-AM 188 and unlabelled AM 188 were added to the perfusate as a bolus initially, followed by a constant rate of infusion at 5, 25, 125, 500 or 1000 microg/min to achieve initial target perfusate concentrations of 1, 5, 25, 100 or 200 microg/mL, respectively. During the 130 min over which AM 188 was infused, urine was collected in 10 min intervals (commencing 10 min after the bolus dose) and perfusate was collected at the mid-point of these intervals to permit calculation of the renal clearance (CLR) of AM 188. Binding of AM 188 in perfusate, measured using ultrafiltration, was negligible. 3. The bolus dose and infusion regimen produced relatively stable AM 188 concentrations in perfusate in the 5, 25 and 125 micro g/min groups and progressively increasing concentrations in the 500 and 1000 microg/min groups. High-pressure liquid chromatography analysis of IPK perfusate and urine suggested that there was no or negligible metabolism of AM 188 in the kidney. The CLR/GFR ratio for AM 188 (mean+/-SD) was 5.76 +/- 1.57, 5.99 +/- 0.52, 6.02 +/- 1.47, 3.38 +/- 0.26 and 1.08 +/- 0.42 in the 5, 25, 125, 500 and 1000 microg/min groups, respectively, showing significant reductions at the two highest infusion rates (P < 0.05). Although there was no difference between the five groups in the distribution of AM 188 between kidney tissue and perfusate (KT/P), at the end of perfusion the corresponding urine-to-tissue concentration ratio declined significantly in the 1000 microg/min group. 4. AM 188 undergoes substantial net renal secretion over a wide range of perfusate concentrations. A reduction in renal clearance at perfusate concentrations above 25 microg/mL could be due to saturation of carrier-mediated transport at the brush border membrane and/or a solubility limitation leading to precipitation of AM 188 in tubular cells and/or tubular urine.
Publisher: Elsevier BV
Date: 02-2004
DOI: 10.1016/S0731-7085(03)00573-9
Abstract: A range of analytical methods exist for the determination of paracetamol in biological fluids. However, to understand the fate of paracetamol and the effect of other drugs on its disposition in vivo, the major metabolites require quantification in urine and plasma. A method to simultaneously quantify paracetamol, paracetamol glucuronide (PG) and paracetamol sulphate (PS) in plasma and urine with superior sensitivity is therefore desired, especially if the volume of plasma available is low. A simple isocratic reverse phase high-performance liquid chromatography (HPLC) assay with spectrophotometric detection has been developed. The method, requiring only 100 microl of plasma and 50 microl of urine, utilizes a reversed-phase C18 column, a wavelength of 254 nm for detection and a mobile phase composed of potassium dihydrogen orthophosphate (0.1 M)-isopropanol-tetrahydrofuran (THF) (100:1.5:0.1, v/v/v) adjusted to pH 3.7 with phosphoric acid. The method is sensitive and linear in plasma within a concentration range from 0.4 to 200 microM for paracetamol, PG and PS. For PG and PS in urine, the method is sensitive and linear within a concentration range from 100 to 20,000 microM. Over these ranges, accuracy and precision were less than 12%. The assay has been used to measure concentrations of paracetamol and the two metabolites in plasma collected by finger-prick s ling and of the metabolites in urine from healthy volunteers administered a single oral dose of 1000 mg of paracetamol.
Publisher: Oxford University Press (OUP)
Date: 08-10-2009
DOI: 10.1093/NDT/GFN588
Abstract: Anaemia is a common complication associated with haemodialysis and is usually managed by treatment with recombinant human erythropoietin (rHuEPO). However, many patients remain hyporesponsive to rHuEPO treatment despite adequate iron therapy. The effect of L-carnitine administration on rHuEPO dose and/or haematocrit in haemodialysis patients has been previously reported with equivocal results. This study examined the relationship between endogenous carnitine pool composition and rHuEPO requirements in long-term haemodialysis patients. Pre-dialysis blood s les were collected from 87 patients and analysed for plasma L-carnitine and in idual acylcarnitine levels by LCMS/MS. As an indication of rHuEPO responsiveness, erythropoietin resistance index (ERI) was calculated as rHuEPO dose/kg/week normalized for haemoglobin levels. A significant negative correlation between L-carnitine levels and ERI was found (P = 0.0421). All patients categorized as high ERI (>0.02 microg/kg/week/gHb) exhibited subnormal L-carnitine levels ( 30 microM) displayed low ERI values (<0.02 microg/kg/week/gHb). More importantly, the ratio of non-acetyl acylcarnitines/total carnitine was significantly positively correlated with ERI (P = 0.0062). These data illustrate the relationship between carnitine levels and response to rHuEPO treatment in haemodialysis patients, in particular, the importance of the proportion of long-chain acylcarnitines within the plasma carnitine pool. This proportion may be more indicative of the response to L-carnitine supplementation than absolute L-carnitine levels alone.
Publisher: Bentham Science Publishers Ltd.
Date: 10-2005
DOI: 10.2174/138920005774330611
Abstract: The present study was designed to investigate the hepatic disposition of the prodrug AM365 and the generated antiviral guanosine analogue, AM188 in the isolated perfused rat liver (IPL). The livers of rats (n=12) were isolated and perfused with Krebs-Henseleit pH 7.4 buffer to which AM365 was added as a bolus to achieve an initial perfusate concentration of 22.4 micromol/L. During the 120-min period after administration of AM365, bile was collected in 10-min intervals and perfusate was collected at the mid-point of these intervals. Concentrations of AM365 and AM188 in perfusate and bile were quantified by HPLC. Following administration of AM365, its concentration in perfusate declined and the concentration of AM188 increased the sum of the molar concentrations remained constant. The clearance and hepatic extraction ratio of AM365 were 3.3+/-2.4 mL/min and 0.110+/-0.079, respectively. The cumulative amount of AM365 excreted in bile during the 120-min perfusion period was approximately 0.21% of the bolus dose, and 0.36% of the total amount of AM365 cleared by the liver during the period. The cumulative amount of AM188 excreted in bile was about 0.48% of the total amount of AM188 formed during the perfusion period. In conclusion, AM365 was metabolised to AM188, which appeared to be the only metabolite and was not further biotransformed. The biliary excretion of AM365 and AM188 was negligible.
Publisher: Bentham Science Publishers Ltd.
Date: 10-2006
DOI: 10.2174/138920006778520561
Abstract: L-Carnitine has important roles in intermediary metabolism and patients with end-stage renal disease who are undergoing hemodialysis may develop a secondary L-carnitine deficiency. The extent of accumulation of the metabolites trimethylamine and trimethylamine-N-oxide when L-carnitine is administered orally has not been investigated previously in this population. Oral L-carnitine at a dose of 1 g daily was administered for twelve days to six patients with end-stage renal disease undergoing hemodialysis thrice weekly. Pre-dialysis plasma concentrations of L-carnitine (mean +/- SD) increased significantly (P < 0.05) from day 1 (baseline 32.4 +/- 6.1 microM) to day 8 (66.1 +/- 13.8 microM) remaining constant thereafter. Although plasma levels of trimethylamine remained unaltered, the pre-dialysis plasma concentrations of trimethylamine-N-oxide increased significantly (P < 0.05) from day 1 (289.1 +/- 236.1 microM) to day 12 (529.0 +/- 237.9 microM). The hemodialysis clearances for L-carnitine, trimethylamine and trimethylamine-N-oxide were 14.3 +/- 8.2, 14.1 +/- 10.6 and 12.4 +/- 5.4 L/h, respectively, indicating their efficient removal by dialysis. Oral administration of L-carnitine at a dose of 1 g daily increases plasma concentrations of this substance to physiological levels in patients with end-stage renal disease who are undergoing hemodialysis. However, concerns about the possible deleterious consequences of such a dosage regimen still remain given that plasma concentrations of trimethylamine-N-oxide were continually rising and approximately doubled in a two-week period.
Publisher: Elsevier BV
Date: 03-2004
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.COLSURFB.2006.03.002
Abstract: Interaction forces, deformation and nano-rheology of in idual red blood cells in physiologically relevant solution conditions have been determined by colloid probe atomic force microscopy (AFM). On approach of the physically immobilised cell and silica glass spherical probe surfaces, deformation of the red blood cell was observed in the force curves. At low levels of deformation, spring constants were determined in the range 3-6 m Nm(-1), whereas for higher levels of deformation, the forces increase non-linearly and on retraction, significant force curve hysteresis is observed (i.e. lower forces upon retraction). The extent of force curve hysteresis was dependent on both the drive velocity and loading force, typical of a viscoelastic system. The response of the red blood cell has been described by viscoelastic theory, where the short and long time scale elastic moduli and relaxation times are determined, i.e. the cell's nano-rheological properties elucidated. In addition to a time independent elastic modulus of 4.0 x 10(3)Nm(-2) at low levels of deformation, time-dependent elastic moduli ranges are observed (3.5 x 10(4) to 5.5 x 10(4)Nm(-2) at intermediate levels of deformation and 1.5 x 10(5) to 3.0 x 10(5)Nm(-2) at higher levels of deformation). That is, one elastic and more than one viscoelastic response to the red blood cell deformation is evident, which is considered to reflect the cellular structure.
Publisher: ASMEDC
Date: 2004
Abstract: There are many domestic applications where a small amount of liquid needs to be applied to a defined small area under strict conditions. In some cases, the sprayed materials are toxic and expensive, and excessive spray will lead to potential damage to other materials and harm to human beings. A controlled micro atomizer is designed by integrating an electronic and mechanical system with adjustable capability to tune the volume. The geometrical dimension of the atomizer is optimized to deliver a right amount of liquid to a predetermined area. To study the influence of atomizer design and air velocity, the sprays issuing from different atomizers of various dimensions are investigated theoretically and computationally under various external flow conditions. It is found that a controlled atomizer can be developed by optimizing the nozzle design.
Publisher: Wiley
Date: 23-12-2013
DOI: 10.1111/FCT.12077
Publisher: Elsevier BV
Date: 12-1990
DOI: 10.1016/0014-2999(90)94181-V
Abstract: The effects of domperidone on the electrical response of the cockroach salivary gland to applied dopamine and to nerve stimulation have been investigated. Dopamine and nerve stimulation induced a hyperpolarization of the salivary gland acinar cells, which was occasionally followed by a depolarization. At 1 and 10 microM domperidone had no effect on the responses however, at higher concentrations domperidone (50 and 100 microM) potentiated the hyperpolarization induced by both dopamine and nerve stimulation. Domperidone (50 microM) also potentiated the hyperpolarization induced by 5-HT. Thus the potentiation probably results from a post synaptic action independent of either the dopamine or 5-hydroxytryptamine receptor. In addition, domperidone (50 and 100 microM) had two delayed effects one, presynaptic, led to a reduction in the response to nerve stimulation the other, postsynaptic, led to the abolition of the depolarizing phase of the response.
Publisher: Wiley
Date: 06-2000
Publisher: Wiley
Date: 08-1990
Abstract: Ibuprofen is a chiral drug which is used clinically as a racemate. The pharmacological properties of ibuprofen reside almost exclusively with the S(+)-enantiomer. However, a portion of R(-)-ibuprofen is metabolically inverted to its pharmacologically active, mirror-image form. To investigate the influence of increasing dose of racemic ibuprofen on the pharmacokinetics of its in idual enantiomers, four healthy male volunteers were given racemic ibuprofen (200, 400, 800, and 1200 mg), orally, on four occasions. The study was conducted using a balanced cross-over design. The extent of absorption of ibuprofen, as assessed by the total urinary recovery of ibuprofen and its metabolites, was extensive and independent of the administered dose. At all four doses, the area under the total and unbound plasma concentration-time curves (AUC and AUCu, respectively), and the unbound fraction in plasma, were significantly greater for the S(+)-enantiomer. With increasing ibuprofen dose, there was a less than proportional increase in the AUC of each enantiomer, while the AUCu for both enantiomers increased in direct proportion to the administered dose. The time-averaged unbound fraction of each enantiomer increased significantly with increasing dose, which caused the non-linearity between AUC and dose. It was predicted that the metabolic intrinsic clearance of each enantiomer, and the fraction of R(-)-ibuprofen which was metabolically inverted to S(+)-ibuprofen, was independent of the administered dose.
Publisher: Bentham Science Publishers Ltd.
Date: 06-2005
Abstract: Trimethylamine (TMA) is a volatile tertiary aliphatic amine that is derived from the diet either directly from the consumption of foods containing TMA, or by the intake of food containing precursors to TMA such as trimethylamine-N-oxide (TMNO), choline and L-carnitine. Following oral absorption in humans, TMA undergoes efficient N-oxidation to TMNO, a reaction catalyzed by the flavin-containing monooxygenase (FMO) isoform 3 enzyme. TMNO subsequently undergoes excretion in the urine, although, evidence also suggests that metabolic retro-reduction of TMNO can occur. Whilst the pharmacokinetics of TMA and TMNO has not been fully elucidated in humans, a number of studies provide information on the likely fate of dietary derived TMA. Trimethylaminuria is a condition that is characterized by a deficiency in FMO3 enzyme activity, resulting in the excretion of increased amounts of TMA in bodily fluids such as urine and sweat, and breath. A human FMO3 database has been established and currently twenty-eight variants of the FMO3 gene have been reported including twenty-four missense, three nonsense, and one gross deletion mutation. Whilst TMA and TMNO are generally regarded as non-toxic substances, they are of clinical interest because of their potential to form the carcinogen N-nitrosodimethylamine.
Publisher: Wiley
Date: 29-01-2013
DOI: 10.1111/HDI.12021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2000
DOI: 10.1097/00007691-200002000-00028
Abstract: There is widespread recognition that the ingestion of a meal is associated with a number of physiologic changes (gastric pH, gastric emptying, hepatic blood flow, etc.) that can significantly alter the rate and extent of drug absorption. It is also well recognized that the components of food can alter drug absorption through alterations in drug solubility. The nutritional status of a patient can also contribute to variability in the pharmacokinetics of certain drugs. The more recent finding that grapefruit juice can increase the bioavailability of certain drugs, by reducing presystemic intestinal metabolism, has led to renewed interest in the area of 'food-drug interactions.' Particular interest has focused on the effects of the grapefruit flavonoid, naringin, and the furanocoumarin, 6',7'-dihydroxybergamottin, on the activity of intestinal CYP3A4. The possibility that grapefruit juice might affect drug absorption via an interaction with intestinal P-glycoprotein (P-gp) is also being explored. The growing use of herbal extracts and phytopharmaceuticals raises a new challenge-will the use of these products cause changes in the pharmacokinetics of 'conventional' drugs? As a case in point, consider the phytoestrogenic isoflavones, which are being promoted for a number of health benefits. Isoflavones such as genistein and daidzein can inhibit oxidative and conjugative metabolism in vitro and interact with transporters such as P-gp and the canalicular multispecific organic anion transporter. Given that P-gp and canalicular multispecific organic anion transporter are involved in the intestinal absorption and biliary excretion of a wide range of drugs and metabolites, it is reasonable to suspect that isoflavones may alter drug disposition in humans. However, this possibility has not been explored.
No related grants have been discovered for Allan Evans.