ORCID Profile
0000-0003-4733-705X
Current Organisations
Austin Health
,
University of Melbourne
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Publisher: Bioscientifica
Date: 09-1990
Abstract: The isolated perfused rat kidney was used to study the effects of amino-terminal fragments of human parathyroid hormone, hPTH(1–34), bovine parathyroid hormone, bPTH(1–84) and of PTH-related proteins, PTHrP(1–34), PTHrP(1–84), PTHrP(1–108) and PTHrP(1–141) on urinary bicarbonate excretion. PTHrP(1–34) (7 nmol/l), bPTH(1–84) (5·5 nmol/l) and hPTH(1–34) (7 nmol/l) had similar effects in increasing bicarbonate excretion with respect to the control. At lower concentrations (0·7 nmol/l) all PTHrP components, but not hPTH(1–34) or bPTH(1–84) increased bicarbonate excretion significantly. Infusions of PTHrP(1–108) and PTHrP(1–141) at 0·7 nmol/l, while associated with a rise in urinary bicarbonate concentration and excretion during the early stages of perfusion, produced a sharp decline in bicarbonate concentration and excretion in the latter part of perfusion. The different peptides produced no significant differences in glomerular filtration rate, fractional excretion of sodium or urine volume. The absence of substantial differences between the effects of hPTH(1–34) and PTHrP(1–34) are as noted in previous studies. The differences between PTHrP(1–108)/PTHrP(1–141) and PTHrP(1–34) demonstrated here are consistent with (1) the clinical manifestations of acidosis in hyperparathyroidism and alkalosis in humoral hypercalcaemia of malignancy, and (2) an independent action of a component of PTHrP beyond amino acids 1–34. Journal of Endocrinology (1990) 126, 403–408
Publisher: Springer Science and Business Media LLC
Date: 1993
DOI: 10.1007/BF00685678
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.CLINBIOCHEM.2016.11.024
Abstract: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation that combines creatinine and cystatin C is superior to equations that include either measure alone in estimating glomerular filtration rate (GFR). However, whether cystatin C can provide any additional benefits in estimating GFR for Indigenous Australians, a population at high risk of end-stage kidney disease (ESKD) is unknown. Using a cross-sectional analysis from the eGFR Study of 654 Indigenous Australians at high risk of ESKD, eGFR was calculated using the CKD-EPI equations for serum creatinine (eGFRcr), cystatin C (eGFRcysC) and combined creatinine and cystatin C (eGFRcysC+cr). Reference GFR (mGFR) was determined using a non-isotopic iohexol plasma disappearance technique over 4h. Performance of each equation to mGFR was assessed by calculating bias, % bias, precision and accuracy for the total population, and according to age, sex, kidney disease, diabetes, obesity and c-reactive protein. Data were available for 542 participants (38% men, mean [sd] age 45 [14] years). Bias was significantly greater for eGFRcysC (15.0mL/min/1.73m Cystatin C based eGFR equations may not perform well in populations with high levels of chronic inflammation. CKD-EPI eGFR based on serum creatinine remains the preferred equation in Indigenous Australians.
Publisher: Wiley
Date: 12-1991
DOI: 10.1111/J.1440-1681.1991.TB01403.X
Abstract: 1. A rat isolated perfused kidney preparation was utilized to define clearly a renal site of action. The variables measured were perfusate pressure and flow, glomerular filtration rate, urine volume, sodium excretion and potassium excretion. 2. Dextromethorphan (3 nmol/L) and dextrorphan (10 nmol/L) reduced sodium excretion in kidneys from rats on either control or high K+ diet, in the absence of any other measured renal effects. Dextromethorphan (10 nmol/L) produced a decrease in glomerular filtration rate as well as a decrease in sodium excretion. Naloxone (1 mumol/L) inhibited the effect of dextromethorphan on sodium excretion but had no effect when administered alone. 3. The levorotatory opiates levorphanol and levomethorphan, the kappa agonist ketocyclazocine and a range of other opiates had no effect on sodium excretion. 4. The results suggest a renal action specific for dextrorotatory opiates. This renal action is consistent with earlier binding studies suggesting preferential recognition of dextrorotatory opiates.
Publisher: Springer Science and Business Media LLC
Date: 28-03-1996
Abstract: Cremophor EL, a surfactant used in the clinical formulation of cyclosporine and paclitaxel, will reverse the multidrug resistance (MDR) phenotype in vitro. As other MDR modulators can alter the pharmacokinetics of cytotoxic drugs, the aim of this study was to examine the effect of Cremophor and another MDR-reversing surfactant, Tween 80, on the hepatic elimination and biliary excretion of etoposide. Using the isolated perfused rat-liver model with 80 ml recirculating perfusate containing 20% red blood cells and 4% bovine serum albumin, etoposide (1.6 mg) with and without Cremophor (800 or 80 mg) or Tween 80 (80 mg) was given into the perfusate reservoir, and perfusate and bile s les were collected for 3 h. Etoposide was measured by high-performance liquid chromatography (HPLC) and Cremophor was measured using a bioassay. Both surfactants changed the etoposide elimination profile from biphasic to monophasic. High-dose Cremophor increased the AUC (from 334 +/- 23 to 1540 +/- 490 microgram min ml(-1), P<0.05) and decreased the total clearance (from 4.8 +/- 0.3 to 1.1 +/- 0.3 ml/min, P<0.05) and biliary clearance (from 2.6 +/- 1.1 to 0.5 +/- 0.2 ml/min, p<0.05) but decreased the elimination half-life (from 62 +/- 17 to 40 +/- 5 min, P<0.05) and volume of distribution (from 424 +/- 85 to 65 +/- 19 ml, P<0.05). Low-dose Cremophor and Tween 80 caused intermediate effects on these parameters that were statistically significant for total clearance, half-life, and volume of distribution. Cremophor had no adverse effect on liver function, whereas Tween 80 caused haemolysis and cholestasis. The initial high-dose Cremophor perfusate concentration was 0.8 mg/ml, which previous studies have shown to be clinically relevant and close to the optimal level for MDR reversal in vitro (1.0 mg/ml). Cremophor may be a clinically useful MDR modulator, but it may alter the pharmacokinetics of the cytotoxic drug.
Publisher: Springer Science and Business Media LLC
Date: 03-07-2004
DOI: 10.1007/S00280-004-0792-3
Abstract: Paclitaxel, when combined with carboplatin, exhibits a platelet-sparing effect. Paclitaxel is formulated in Cremophor EL (CrEL), which has been shown in preclinical models to reduce haematological toxicity from radiotherapy and chemotherapy. We sought to determine the effect of a 3-h infusion of 20 ml/m2 (equivalent to 175 mg/m2 paclitaxel) CrEL on myelosuppression following carboplatin chemotherapy, and the effect of CrEL on carboplatin pharmacokinetics. A total of 16 patients with locally advanced or metastatic cancer were randomized to receive either CrEL or saline over 3 h prior to carboplatin (area under the curve, AUC, 5-7). Each patient was subsequently crossed over to the other treatment. Blood s les were collected at selected time-points for estimation of platinum AUC and 24-h platinum levels. Full blood counts were obtained three times per week. Of the 16 patients randomized, 15 were evaluable. Myelosuppression was measured by percentage fall at nadir and nadir levels. No significant differences were obtained when comparing CrEL and saline with respect to the above end-points after adjusting for multiple testing. There was no evidence to indicate that CrEL altered the pharmacokinetics of carboplatin. CrEL at this dose and schedule does not appear to be a major contributory factor to the platelet-sparing effect of paclitaxel when combined with carboplatin, nor does it alter the pharmacokinetics of carboplatin.
Publisher: Elsevier BV
Date: 05-2006
DOI: 10.1016/J.BCP.2006.01.020
Abstract: The tyrphostin 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) is a potent and specific inhibitor of EGFR tyrosine kinase whose favourable preclinical profile supports progression towards clinical trials. Microphysiometric evaluation revealed a short ( infinity) (r2=0.979) enabled the prediction of infusion rates and doses for sustained delivery using continuous 6 h infusions, where steady state was reached in 120 min. Plasma levels of AG1478>10 microM were achieved over the duration of the infusion. At the lowest dose, plasma drug levels after the cessation of infusion declined with a half-life of approximately 43 min. EGFR activity, measured both by autophosphorylation and downstream signalling, was inhibited in a dose-dependent manner by injection of AG1478 in mice bearing xenografts of the human glioblastoma cell line U87MG.delta2-7, which expresses a constitutively active variant of the EGF receptor. Taken together, these experiments provide essential data to assess the anti-tumour efficacy of AG1478 and will assist in the rational design of dose regimens for clinical studies.
Publisher: Elsevier BV
Date: 10-2012
Publisher: Oxford University Press (OUP)
Date: 28-10-2013
DOI: 10.1093/CID/CIT704
Abstract: Multidrug-resistant gram-negative bacterial (MDR-GNB) infections of the prostate are an increasing problem worldwide, particularly complicating transrectal ultrasound (TRUS)-guided prostate biopsy. Fluoroquinolone-based regimens, once the mainstay of many protocols, are increasingly ineffective. Fosfomycin has reasonable in vitro and urinary activity (minimum inhibitory concentration breakpoint ≤64 µg/mL) against MDR-GNB, but its prostatic penetration has been uncertain, so it has not been widely recommended for the prophylaxis or treatment of MDR-GNB prostatitis. In a prospective study of healthy men undergoing a transurethral resection of the prostate for benign prostatic hyperplasia, we assessed serum, urine, and prostatic tissue (transition zone [TZ] and peripheral zone [PZ]) fosfomycin concentrations using liquid chromatography-tandem mass spectrometry, following a single 3-g oral fosfomycin dose within 17 hours of surgery. Among the 26 participants, mean plasma and urinary fosfomycin levels were 11.4 ± 7.6 µg/mL and 571 ± 418 µg/mL, 565 ± 149 minutes and 581 ± 150 minutes postdose, respectively. Mean overall prostate fosfomycin levels were 6.5 ± 4.9 µg/g (range, 0.7-22.1 µg/g), with therapeutic concentrations detectable up to 17 hours following the dose. The mean prostate to plasma ratio was 0.67 ± 0.57. Mean concentrations within the TZ vs PZ prostate regions varied significantly (TZ, 8.3 ± 6.6 vs PZ, 4.4 ± 4.1 µg/g P = .001). Only 1 patient had a mean prostatic fosfomycin concentration of <1 µg/g, whereas the majority (70%) had concentrations ≥4 µg/g. Fosfomycin appears to achieve reasonable intraprostatic concentrations in uninflamed prostate following a single 3-g oral dose, such that it may be a potential option for prophylaxis pre-TRUS prostate biopsy and possibly for the treatment of MDR-GNB prostatitis. Formal clinical studies are now required.
Publisher: Elsevier BV
Date: 08-2010
Publisher: Springer Science and Business Media LLC
Date: 02-12-2014
DOI: 10.1038/SC.2014.218
Abstract: Single centre, single ascending dose study. To compare the pharmacokinetics and assess the safety of capromorelin, a compound that has potential to treat constipation following spinal cord injury (SCI), in groups of able-bodied and SCI volunteers. Local population from Victoria, Australia. Following initial screening and baseline blood collections, participants received ascending oral doses (20, 50 and then 100 mg at least 1-week apart) of capromorelin after pre-dose blood collection, followed by blood collections over the following 12 h for pharmacokinetic analysis and 1-week and 4-week follow-up blood collections for safety evaluations. Blood pressure and heart rate were monitored. No serious adverse events were recorded following any dose in either the able-bodied group or the SCI group. There were no abnormal blood pressure or heart rate changes. Minor adverse events resolved quickly without the need for treatment. Pharmacokinetic behaviour was broadly similar between groups, with both exhibiting dose-dependent increases in Cmax and AUC0-∞. The SCI participants showed greater variance in pharmacokinetic parameters and had a slightly delayed Tmax and half-life. Capromorelin at the doses tested was safe and well tolerated in both SCI and able-bodied participants and also showed similar pharmacokinetics with dose-dependent increases in concentration and drug exposure.
Publisher: Oxford University Press (OUP)
Date: 03-07-2015
DOI: 10.1093/NDT/GFV230
Abstract: Hyperfiltration (HF) has been linked to the development of diabetic kidney disease (DKD), but the causative or predictive role of HF in the pathogenesis of DKD still remains unclear. To date, there have been no studies of HF in Indigenous Australians, a population with high rates of both diabetes and end-stage kidney disease. We aimed to compare the characteristics and frequency of HF in Indigenous Australians with and without type 2 diabetes. Indigenous Australian participants, recruited across five pre-defined strata of health, diabetes status and kidney function, had a reference glomerular filtration rate (GFR) measured using plasma disappearance of iohexol [measured GFR(mGFR)] over 4 h. HF was defined in various ways: (i) mGFR > 144 mL/min/1.73 m(2), which is mGFR > 1.96 × SD above the mean of the mGFR in non-diabetic participants with normal albuminuria and normal renal function (mGFR > 90 mL/min/1.73 m(2)) (ii) age-corrected mGFR (>144 mL/min/1.73 m(2)) to account for the effect of ageing on GFR in subjects over 40 years of age with cut-off 1 mL/min/1.73 m(2) lower for every year (iii) mGFR > 144 mL/min, without correction for body surface area or age, as well as (iv) mGFR > 125 mL/min/1.73 m(2), without adjustment for age. A total of 383 Indigenous participants, 125 with and 258 without diabetes, with mGFR > 90 mL/min/1.73 m(2) were studied. The proportion of participants with HF was 7% using mGFR > 144 mL/min/1.73 m(2), 11% using the age-adjusted definition, 19% using mGFR > 144 mL/min and 27% using mGFR > 125 mL/min/1.73 m(2). Diabetes was more common in participants with HF (40-74%) compared with normofiltering participants (28-31%), regardless of the definition of HF. HF exists in Indigenous Australians with and without diabetes. A greater proportion of participants had diabetes in HF group compared with normofiltration group. Long-term follow-up of this cohort is necessary to determine if HF plays a role in the development of DKD and non-DKD.
Publisher: Springer Science and Business Media LLC
Date: 1999
Abstract: Cremophor can alter the pharmacokinetics of cytotoxic drugs, including doxorubicin and etoposide. In view of its presence in the formulation of paclitaxel, the aim of this study was to investigate the influence of Cremophor on the hepatobiliary elimination of paclitaxel. In a recirculating isolated perfused rat-liver system the elimination of 1.7 mg paclitaxel given as a bolus into the perfusate reservoir was monitored in perfusate and bile in controls and after the administration of either 80 or 800 microl Cremophor. The higher dose of Cremophor yields clinically relevant perfusate concentrations. Paclitaxel was measured in perfusate, bile, and liver tissue by high-performance liquid chromatography. Cremophor caused a dose-dependent inhibition of the elimination of paclitaxel, with a statistically significant mean value +/-SD, n=3 (P < 0.05 versus controls Bonferroni t-test) 9-fold increase in AUC (2227+/-106 versus 245+/-40 microg ml(-1) min), 9-fold decrease in total clearance (0.8+/-0.1 versus 7.0+/-1.1 ml/min), and 5-fold increase in elimination half-life (92+/-14 versus 18+/-4 min) being observed after a dose of 800 microl Cremophor. With the addition of Cremophor the amount of paclitaxel remaining after 3 h increased in perfusate from none to 20%, increased in liver tissue from 4% to 18%, and remained constant in bile at 11-13%. In the control group, 86% of the paclitaxel dose was recovered in bile as five putative metabolites, which were measured in paclitaxel equivalents, with the major metabolite. M3 co-eluting with 3'-p-hydroxypaclitaxel. This decreased to 45% of the dose on the addition of Cremophor, and the ratio of M3 to paclitaxel in bile decreased. Cremophor inhibits the hepatic elimination of paclitaxel in the isolated perfused rat liver, primarily by preventing the drug from reaching sites of metabolism and excretion. The presence of Cremophor in the paclitaxel formulation may therefore contribute to the nonlinear pharmacokinetics and pharmacodynamics of paclitaxel.
Publisher: Oxford University Press (OUP)
Date: 10-06-2015
DOI: 10.1093/CID/CIV436
Abstract: Treatment options for prostatitis caused by multidrug-resistant gram-negative bacilli are limited. We report two cases cured with oral fosfomycin and provide a pharmacokinetic analysis of fosfomycin predose concentrations during treatment.
Publisher: Springer Science and Business Media LLC
Date: 19-02-2010
Publisher: Oxford University Press (OUP)
Date: 22-03-2015
DOI: 10.1093/JAC/DKV067
Abstract: As the optimal administration time for fosfomycin peri-procedural prophylaxis is unclear, we sought to determine optimal administration times for fosfomycin peri-procedural prophylaxis. Plasma, peripheral zone and transition zone fosfomycin concentrations were obtained from 26 subjects undergoing transurethral resection of the prostate (TURP), following a single oral dose of 3 g of fosfomycin. Population pharmacokinetic modelling was completed with the Nonparametric Adaptive Grid (NPAG) algorithm (Pmetrics package for R), with a four-compartment model. Plasma and tissue concentrations were simulated during the first 24 h post-dose, comparing these with EUCAST susceptibility breakpoints for Escherichia coli, a common uropathogen. Non-compartmental-determined pharmacokinetic values in our population were similar to those reported in the package insert. Predicted plasma concentrations rapidly increased after the first hour, giving more than 90% population coverage for organisms with an MIC ≤4 mg/L over the first 12 h post-dose. Organisms with higher MICs fared much worse, with organisms at the EUCAST breakpoint being covered for & % of the population at any time. Transitional zone prostate concentrations exceeded 4 mg/L for 90% of the population between hours 1 and 9. Peripheral zone prostate concentrations were much lower and only exceeded 4 mg/L for 70% of the population between hours 1 and 4. Until more precise plasma and tissue data are available, we recommend that fosfomycin prophylaxis be given 1–4 h prior to prostate biopsy. We do not recommend fosfomycin prophylaxis for subjects with known organisms with MICs & mg/L.
Publisher: S. Karger AG
Date: 2005
DOI: 10.1159/000085621
Abstract: i Background: /i Pre-clinically, hyaluronan (HA) has been demonstrated to systemically target chemotherapeutic drugs to tumours while ameliorating treatment toxicities. This study is a preliminary clinical investigation to determine if HA could be safely used in combination with 5-fluorouracil (5-FU) and doxorubicin (DOX). i Methods: /i Thirty patients with metastatic cancer were intravenously administered 500 mg/m sup /sup HA in combination with escalating doses of DOX (30–60 mg/m sup /sup ) or 5-FU (cumulative dose of 1,350–2,250 mg/m sup /sup per cycle). The effect of pre-administration of 20 mg/m sup /sup of folinic acid on HA/5-FU chemotherapy was also investigated. Patients were randomized to receive either HA/chemotherapy or chemotherapy alone in their first treatment cycle and vice versa for the second cycle. Patients received HA and chemotherapy in all subsequent cycles. i Results: /i Treatment was well tolerated, tumour responses were observed and the co-administration of HA did not alter the pharmacokinetics of clinically relevant doses of 5-FU or DOX. i Conclusion: /i High doses of intravenous high-molecular-weight HA can be safely co-administered with clinical doses of chemotherapy without significantly altering the toxicity or pharmacokinetics of the drugs or HA.
Publisher: Wiley
Date: 04-04-2014
DOI: 10.1111/DME.12426
Abstract: It has been proposed that the Chronic Kidney Disease Epidemiology Collaboration formula estimates glomerular filtration rate more accurately than the Modification of Diet in Renal Disease formula. With the very high incidence of diabetes and end-stage kidney disease in Indigenous Australians, accurate estimation of glomerular filtration rate is vital in early detection of kidney disease. We aimed to assess the performance of the Chronic Kidney Disease Epidemiology Collaboration, Modification of Diet in Renal Disease and Cockcroft-Gault formulas in Indigenous Australians with and without diabetes. Indigenous Australians with (n = 224) or without (n = 340) Type 2 diabetes had a reference glomerular filtration rate measure using plasma disappearance of iohexol (measured glomerular filtration rate) over 4 h. Serum creatinine was measured by an enzymatic method. Performance was assessed by bias (measured glomerular filtration rate - estimated glomerular filtration rate) and accuracy (percentage of estimated glomerular filtration rate within 30% of measured glomerular filtration rate). The median measured glomerular filtration rate (interquartile range) in participants with or without diabetes was 97 (68-119) and 108 (90-122) ml min(-1) 1.73 m(-2) , respectively. The Chronic Kidney Disease Epidemiology Collaboration formula had smaller bias and greater accuracy than the Modification of Diet in Renal Disease and Cockcroft-Gault formulas overall, for participants both with and without diabetes. However, for estimated glomerular filtration rate > 90 ml min(-1) 1.73 m(-2) , the Chronic Kidney Disease Epidemiology Collaboration formula had greater bias in participants with diabetes, underestimating measured glomerular filtration rate by 7.4 vs. 1.0 ml min(-1) 1.73 m(-2) in those without diabetes. The Chronic Kidney Disease Epidemiology Collaboration formula was less accurate across the whole range of estimated glomerular filtration rates in participants with vs. those without diabetes (87.1% vs. 93.3%). The Chronic Kidney Disease Epidemiology Collaboration formula outperforms the Modification of Diet in Renal Disease and Cockcroft-Gault formulas overall in Indigenous Australians with and without diabetes. However, the Chronic Kidney Disease Epidemiology Collaboration formula has greater bias in people with diabetes compared with those without diabetes, especially in those with normal renal function.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2014
Publisher: Wiley
Date: 1987
DOI: 10.1111/J.1440-1681.1987.TB00956.X
Abstract: The aim of this study was to determine whether the kaliuresis associated with glucocorticoids is due to a direct tubular action or is secondary to effects of glucocorticoids on distal tubule flow. A whole kidney technique was used to avoid the problem, inherent in microperfusion and micropuncture studies, of deciding whether (all) the appropriate nephron segment(s) are being studied. The method used was to determine the best whole kidney measure of distal tubule flow (the independent variable) by correlating this with the dependent variable (potassium excretion, corrected for differences in plasma potassium, UkV/PIK+) in conscious intact and adrenalectomized control and potassium-adapted rats. After an intragastric potassium chloride load, the correlation of UkV/PIK+ with UkV + UNaV was better than with either UNaV or UV, as measures of distal tubule flow. From the relationship a measure of potassium excretion independent of distal tubule flow can thus be calculated as UkV/PIK+ ided by (UkV + UNaV), defined as UK#. Measurement of UK# clearly demonstrates decreases in potassium excretion with adrenalectomy and increases in potassium excretion with aldosterone and in the potassium-adapted rat, consistent with described changes in potassium secretion. In contrast, with dexamethasone treatment, whilst there was an increase in UkV and UkV/PIK+, there was no change in UK# either in the control of potassium-adapted rats. These results suggest that the kaliuretic effect of dexamethasone cannot be attributed to direct tubular effects of glucocorticoids but rather can be explained by its effect on distal tubule flow.
Publisher: Elsevier BV
Date: 04-2015
Publisher: Wiley
Date: 09-1988
DOI: 10.1111/J.1440-1681.1988.TB01121.X
Abstract: 1. This study examines the contribution of an increased distal tubule flow and of aldosterone to the handling of a potassium load in conscious rats with renal failure induced by subtotal nephrectomy or by gentamicin on a control of high K+ diet. 2. Glomerular filtration rate was reduced by subtotal nephrectomy to 40% and by gentamicin treatment to 60% of control. Subtotal nephrectomy induced significant hypertrophy of glomeruli and proximal and distal tubules, but gentamicin did not. Both experimental groups had a normal iothalamate space and plasma potassium after a 20 h fast. 3. Two hours after an acute KCl load rats with renal failure excreted less potassium than control rats. There was also a lesser natriuretic effect of KCl in the renal failure groups. 4. A high K+ diet, given for 5-7 days, increased excretion of an acute KCl load in control rats and rats with renal failure. 5. (UNaV + UKV) was used as an estimate of distal tubule flow. Potassium excretion, related to distal tubule flow, was similar in the renal failure and control rats when on the same diet. This is consistent with potassium excretion being strongly, but not necessarily solely, dependent on distal flow. 6. Adrenalectomy reduced, and aldosterone restored, potassium excretion in the renal failure and control groups. This suggests a role for aldosterone in excretion of an acute potassium load with this degree of renal failure.
Publisher: Springer Science and Business Media LLC
Date: 2002
DOI: 10.1007/S00280-001-0381-7
Abstract: Two new series of platinum complexes with cytotoxic activity in vivo are [Pt(NRCH2)2L2], (R=polyfluorophenyl, L=pyridine or substituted pyridine) and [Pt(NRCH2CH2NR'2)2L(X)], (R, L as before R'=Me or Et, X=halogen). The aim of this study was to determine the pharmacokinetics and excretion in mice and in isolated perfused rat livers of a representative compound from each class, respectively: Pt103 (R=p-HC6F4, L=pyridine) and Pt109 (R, L as for Pt103, R'=Et, X=I). Mice were given intraperitoneal injections of active doses of Pt103, Pt109, or cisplatin in a variety of vehicles. Blood was s led at several times to 48 h. Some mice were placed in metabolic cages where urine and feces were collected. In isolated, perfused rat livers, perfusate and bile were collected following a dose of Pt103, cisplatin or carboplatin. Platinum was measured in blood, urine, feces, or perfusate by atomic absorption spectroscopy. Three vehicles used were peanut oil, dimethyl sulphoxide, and saline/Tween 20. In contrast to renal excretion of over 70% for cisplatin in saline, urinary excretion of platinum was less than 24% of a dose of Pt109 in peanut oil, less than 21% of P103 in DMSO, and only 4% for Pt103 in peanut oil. Over 60% of Pt103 was eliminated in mouse feces, and 57% was excreted in bile from rat liver. Plasma protein binding of Pt109 was greater than 90% at 6 h following administration in mice. In contrast to cisplatin and carboplatin, representatives of two new classes of platinum anticancer agents undergo minimal renal elimination, but are excreted mainly in the bile and feces. If a platinum complex with a similar excretion profile was introduced into the clinic, there might be a therapeutic advantage in terms of drug toxicity and combination therapy with other cytotoxics.
No related grants have been discovered for ANDREW G ELLIS.