ORCID Profile
0000-0001-9538-549X
Current Organisation
Monash Institute of Pharmaceutical Sciences
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Synthesis of Materials | Animal Physiology - Cell | Pharmaceutical sciences | Protein Trafficking | Pharmacology and Pharmaceutical Sciences | Pharmacology and pharmaceutical sciences | Pharmaceutical delivery technologies | Functional Materials | Medicinal and Biomolecular Chemistry | Nanotechnology | Pharmaceutical Sciences | Proteins and Peptides | Nanobiotechnology |
Expanding Knowledge in the Chemical Sciences | Expanding Knowledge in the Biological Sciences | Expanding Knowledge in Technology | Human Pharmaceutical Treatments (e.g. Antibiotics) | Expanding Knowledge in the Medical and Health Sciences
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.EJPB.2022.10.019
Abstract: Dietary lipids, highly lipophilic drugs, antigens and immune cells are transported from the intestine to the mesenteric lymph nodes (MLNs) via mesenteric lymphatic vessels. Recently our lab reported that the mesenteric lymphatic vessels become highly branched and leak lymph to the surrounding mesenteric adipose tissue (MAT) in mice and humans with obesity, promoting insulin resistance. This study aimed to investigate the impact of obesity-associated mesenteric lymph leakage on the trafficking of a dietary lipid (oleic acid), lipophilic drug (cyclosporin A) and antigen (ovalbumin) from the intestine to MLNs. C57BL/6J mice were fed a control fat diet (CFD), or a high fat diet (HFD) for up to 35 weeks leading to obesity and impaired glucose tolerance.
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.EJPB.2021.09.004
Abstract: Vaccines are a powerful health intervention but there is still an unmet need for effective preventative and therapeutic vaccines for many diseases such as cancer and infections. Interstitial (e.g. subcutaneous (SC)) injection in nano-sized carriers such as high density lipoproteins (HDLs) can improve the access of vaccine subunit antigens or adjuvants to target immune cells in the lymphatics and potentiate vaccination responses such as cytotoxic T lymphocyte (CTL) responses (Kuai et al., 2016, 2018 Qian et al., 2016). Here we examined how cholesterol conjugation to the vaccine adjuvant CpG, and incorporation into HDL, changes lymphatic absorption and association with, and processing by, dendritic cells (DCs), ultimately influencing adjuvant efficacy. We investigated the lymphatic disposition of cholesterol conjugated CpG incorporated into HDL (HDL(Chol-CpG-Cy5)) relative to free cholesterol conjugated CpG (Chol-CpG-Cy5) and unconjugated CpG (free CpG-Cy5) after SC administration in rats and mice. HDL (Chol-CpG-Cy5) and Chol-CpG-Cy5 differentially altered CpG absorption into lymph vs. blood, but surprisingly resulted in similarly higher LN accumulation relative to free CpG. The mechanism of access of Chol-CpG-Cy5 into lymph might be partly due to association with endogenous HDL at the injection site followed by transport into lymph in association with the HDL. To measure CpG association with and processing by DCs and the strength of the immune response, mice were vaccinated with free ovalbumin (OVA) co-administered with the different CpG constructs. There were significant changes in DC activation that were reflective of the trend in LN accumulation at 24 h post-vaccination. However, T cell responses at 24 h and 7 days post-vaccination were not significantly different across the CpG groups although the response was less variable for Chol-CpG-Cy5 compared to free CpG Cy5 and also HDL(Chol-CpG-Cy5) - despite similar LN accumulation with the latter. Overall, our data indicate that cholesterol conjugation and incorporation into HDL increases adjuvant lymph disposition and DC activation.
Publisher: Elsevier BV
Date: 04-2022
Publisher: American Chemical Society (ACS)
Date: 09-11-2017
DOI: 10.1021/ACS.MOLPHARMACEUT.7B00660
Abstract: Lipid based formulations (LBFs) are a promising formulation strategy for many poorly water-soluble drugs and have been shown previously to enhance the oral exposure of CP-532,623, an oral cholesteryl ester transfer protein inhibitor. In the current study, an in vitro lipid digestion model was used to probe the relationship between drug solubilization and supersaturation on in vitro dispersion and digestion of LBF containing long chain (LC) lipids and drug absorption in vivo. After in vitro digestion of LBF based on LC lipids, the proportion of CP-532,623 maintained in the solubilized state in the aqueous phase of the digest was highest in formulations containing Kolliphor RH 40, and in most cases outperformed equivalent formulations based on MC lipids. Subsequent administration of the LC-LBFs to beagle dogs resulted in reasonable correlation between concentrations of CP-532,623 measured in the aqueous phase of the in vitro digest after 30 min digestion and in vivo exposure (AUC) however, the LC-LBFs required greater in vitro drug solubilization to elicit similar in vivo exposure when compared to previous studies with MC-LBF. Although post digestion solubilization was enhanced in LC-LBF compared to MC-LBF, equilibrium solubility studies of CP-532,623 in the aqueous phase isolated from blank lipid digestion experiments revealed that equilibrium solubility was also higher, and therefore supersaturation lower. A revised correlation based on supersaturation in the digest aqueous phase and drug absorption was therefore generated. A single, linear correlation was evident for both LC- and MC-LBF containing Kolliphor RH 40, but this did not extend to formulations based on other surfactants. The data suggest that solubilization and supersaturation are significant drivers of drug absorption in vivo, and that across formulations with similar formulation composition good correlation is evident between in vitro and in vivo measures. However, across dissimilar formulations, solubilization and supersaturation alone are not sufficient to explain drug exposure and other factors also likely play a role.
Publisher: MDPI AG
Date: 20-09-2022
DOI: 10.20944/PREPRINTS202209.0288.V1
Abstract: The repurposing of licenced drugs for use against COVID-19 is one of the most rapid ways to develop new and alternative therapeutic options to manage the ongoing pandemic. Given the approximately 8,000 licenced compounds available from Compounds Australia that can be screened, this paper demonstrates the utility of commercially-available ex vivo/3D airway and alveolar tissue models. These models are a closer representation of in vivo studies compared to in vitro models, but retain the benefits of rapid in vitro screening for drug efficacy. We demonstrate that several existing drugs appear to show anti-SARS-CoV-2 activity against both Delta and Omicron Variants of Concern in the airway model. In particular, fluvoxamine, as well as aprepitant, everolimus, and sirolimus have virus reduction efficacy comparable to the current standard of care (remdesivir, molnupiravir, nirmatrelvir). Whilst these results are encouraging, further testing and efficacy studies are required before clinical use can be considered.
Publisher: Springer Science and Business Media LLC
Date: 23-09-2006
Publisher: Elsevier BV
Date: 11-2020
Publisher: American Chemical Society (ACS)
Date: 27-03-2013
DOI: 10.1021/MP3006566
Abstract: The oral bioavailability of poorly water-soluble drugs (PWSD) is often significantly enhanced by coadministration with lipids in food or lipid-based oral formulations. Coadministration with lipids promotes drug solubilization in intestinal mixed micelles and vesicles, however, the mechanism(s) by which PWSD are absorbed from these dispersed phases remain poorly understood. Classically, drug absorption is believed to be a product of the drug concentration in free solution and the apparent permeability across the absorptive membrane. Solubilization in colloidal phases such as mixed micelles increases dissolution rate and total solubilized drug concentrations, but does not directly enhance (and may reduce) the free drug concentration. In the absence of changes to cellular permeability (which is often high for lipophilic, PWSD), significant changes to membrane flux are therefore unexpected. Realizing that increases in effective dissolution rate may be a significant driver of increases in drug absorption for PWSD, we explore here two alternate mechanisms by which membrane flux might also be enhanced: (1) collisional drug absorption where drug is directly transferred from lipid colloidal phases to the absorptive membrane, and (2) supersaturation-enhanced drug absorption where bile mediated dilution of lipid colloidal phases leads to a transient increase in supersaturation, thermodynamic activity and absorption. In the current study, collisional uptake mechanisms did not play a significant role in the absorption of a model PWSD, cinnarizine, from lipid colloidal phases. In contrast, bile-mediated dilution of model intestinal mixed micelles and vesicles led to drug supersaturation. For colloids that were principally micellar, supersaturation was maintained for a period sufficient to promote absorption. In contrast, for primarily vesicular systems, supersaturation resulted in rapid drug precipitation and no increase in drug absorption. This work suggests that ongoing dilution by bile in the gastrointestinal tract may invoke supersaturation in intestinal colloids and promote absorption, and thus presents a new mechanism by which lipids may enhance the oral absorption of PWSD.
Publisher: Elsevier BV
Date: 07-2021
Publisher: MDPI AG
Date: 31-10-2022
DOI: 10.3390/V14112417
Abstract: The repurposing of licenced drugs for use against COVID-19 is one of the most rapid ways to develop new and alternative therapeutic options to manage the ongoing pandemic. Given circa 7817 licenced compounds available from Compounds Australia that can be screened, this paper demonstrates the utility of commercially available ex vivo/3D airway and alveolar tissue models. These models are a closer representation of in vivo studies than in vitro models, but retain the benefits of rapid in vitro screening for drug efficacy. We demonstrate that several existing drugs appear to show anti-SARS-CoV-2 activity against both SARS-CoV-2 Delta and Omicron Variants of Concern in the airway model. In particular, fluvoxamine, as well as aprepitant, everolimus, and sirolimus, has virus reduction efficacy comparable to the current standard of care (remdesivir, molnupiravir, nirmatrelvir). Whilst these results are encouraging, further testing and efficacy studies are required before clinical use can be considered.
Publisher: Wiley
Date: 02-08-2016
Abstract: First-pass hepatic metabolism can significantly limit oral drug bioavailability. Drug transport from the intestine through the lymphatic system, rather than the portal vein, circumvents first-pass metabolism. However, the majority of drugs do not have the requisite physicochemical properties to facilitate lymphatic access. Herein, we describe a prodrug strategy that promotes selective transport through the intestinal lymph vessels and subsequent release of drug in the systemic circulation, thereby enhancing oral bioavailability. Using testosterone (TST) as a model high first-pass drug, glyceride-mimetic prodrugs incorporating self-immolative (SI) spacers, resulted in remarkable increases (up to 90-fold) in TST plasma exposure when compared to the current commercial product testosterone undecanoate (TU). This approach opens new opportunities for the effective development of drugs where oral delivery is limited by first-pass metabolism and provides a new avenue to enhance drug targeting to intestinal lymphoid tissue.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Frontiers Media SA
Date: 25-04-2022
Publisher: Springer Science and Business Media LLC
Date: 03-2007
DOI: 10.1038/NRD2197
Abstract: Highly potent, but poorly water-soluble, drug candidates are common outcomes of contemporary drug discovery programmes and present a number of challenges to drug development - most notably, the issue of reduced systemic exposure after oral administration. However, it is increasingly apparent that formulations containing natural and/or synthetic lipids present a viable means for enhancing the oral bioavailability of some poorly water-soluble, highly lipophilic drugs. This Review details the mechanisms by which lipids and lipidic excipients affect the oral absorption of lipophilic drugs and provides a perspective on the possible future applications of lipid-based delivery systems. Particular emphasis has been placed on the capacity of lipids to enhance drug solubilization in the intestinal milieu, recruit intestinal lymphatic drug transport (and thereby reduce first-pass drug metabolism) and alter enterocyte-based drug transport and disposition.
Publisher: Springer Science and Business Media LLC
Date: 02-12-2014
DOI: 10.1007/S11095-014-1579-9
Abstract: Recent studies have demonstrated the potential for a triglyceride (TG) mimetic prodrug to promote the delivery of mycophenolic acid (MPA) to the lymphatic system. Here, the metabolic pathways that facilitate the lymphatic transport of the TG prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) were examined to better inform the design of next generation prodrugs. In vitro hydrolysis experiments in simulated intestinal conditions and in vivo rat lymphatic transport experiments were conducted in the presence and absence of orlistat and A922500 (inhibitors of lipolysis and TG re-esterification, respectively), to evaluate the importance of 2-MPA-TG digestion and re-esterification of 2-MPA-MG (the 2-monoglyceride derivative) in promoting lymphatic transport. 2-MPA-TG was rapidly hydrolysed to 2-MPA-MG on incubation with fresh bile and pancreatic fluid (BPF), but not in simulated gastric fluid, heat-inactivated BPF or BPF + orlistat. Orlistat markedly decreased lymphatic transport and systemic exposure of 2-MPA-TG derivatives suggesting that inhibition of pancreatic lipase hindered luminal digestion and absorption of the prodrug. A922500 also significantly decreased lymphatic transport of 2-MPA-TG but redirected MPA to the portal blood, suggesting that hindered re-acylation of 2-MPA-MG resulted in intracellular degradation. Incorporation into TG deacylation-reacylation pathways is a critical determinant of the utility of lymph directed TG-mimetic prodrugs.
Publisher: MyJove Corporation
Date: 06-03-2015
DOI: 10.3791/52389
Publisher: American Chemical Society (ACS)
Date: 10-06-2013
DOI: 10.1021/MP400035Z
Abstract: Co-administration of poorly water-soluble drugs (PWSD) with dietary or formulation lipids stimulates the formation of lipid colloidal phases such as vesicular and micellar species, and significantly expands the drug solubilization capacity of the small intestine. The mechanism of drug absorption from the solubilizing phases, however, has not been fully elucidated. Recently, we observed that drug supersaturation may be triggered during endogenous processing of lipid colloidal phases containing medium-chain lipid digestion products and that this may represent a mechanism to reverse the reduction in thermodynamic activity inherent in drug solubilization and thereby enhance absorption. The current studies expand these preliminary findings and explore the supersaturation tendency of five model PWSD during endogenous processing of intestinal colloidal phases containing long-chain lipid digestion products. Bile-lipid concentration ratios progressively increase during colloid transit through the gastrointestinal tract due to biliary dispersion of lipid digestion products and lipid absorption. The supersaturation potential was therefore evaluated under conditions of increasing bile and decreasing lipid concentrations and was found to be greater for the basic drugs cinnarizine (CIN) and halofantrine (HF), than the neutral drugs fenofibrate (FF) and danazol (DAN), and acidic drug meclofenamic acid (MFA). Assessment of intestinal absorptive flux using rat jejunal perfusion experiments subsequently showed that the absorption enhancement afforded by bile dilution of lipid colloidal phases was greater for CIN than DAN. The results confirm that bile plays a significantly greater role in the absorption of CIN (a weak base) from long-chain intestinal colloids when compared to DAN (an uncharged molecule) and that the difference reflects a greater propensity for supersaturation as intestinal colloids are dispersed and diluted by bile. The data suggest that coadministered digestible lipids may be particularly suited to enhance the absorption of poorly water-soluble weak bases.
Publisher: Springer Science and Business Media LLC
Date: 16-07-2010
Publisher: American Chemical Society (ACS)
Date: 29-09-2016
DOI: 10.1021/ACS.MOLPHARMACEUT.6B00504
Abstract: Vesicular and colloidal delivery systems can be designed to control drug release spatially and temporally to improve drug efficacy and side effect profiles. Niosomes (vesicles prepared from nonionic surfactants in aqueous media) are gaining interest as an alternative vesicular delivery system as they offer advantages such as biocompatibility, chemical stability, low cost, high purity, and versatility. However, the physical stability of niosomes, like other vesicular systems, is limited by vesicle fusion, aggregation, and leakage. Proniosomes (dehydrated powder or gel formulations that spontaneously form niosomes on hydration with aqueous media) can overcome these physical stability problems and are more convenient for sterilization, storage, transport, distribution, and dosing. Proniosomes have mostly been explored for their potential to enhance transdermal and oral absorption. In this study we assess, for the first time, the potential for hydrated proniosomes to sustain systemic exposure and therapeutic effect after intravenous delivery. Proniosomes carrying the anti-inflammatory drug, flurbiprofen, were prepared by spraying different nonionic surfactants (span 20, span 40, and span 60 in varying ratios with span 80) and cholesterol onto a sorbitol carrier. The proniosome powders were characterized for surface morphology and flow properties. Niosome formation was assessed at three different hydration temperatures (25, 37, and 45 °C), and the niosomes were assessed for vesicle size, entrapment efficiency, and sterility. OLP proniosomes prepared with a high ratio of span 80 to span 20 were found to spontaneously form vesicles of small size and high drug loading on hydration with aqueous media. The OLP derived niosomes successfully sustained in vitro drug release, in vivo pharmacokinetics, and the anti-inflammatory effect of flurbiprofen in an acute (rat paw edema) model of inflammation when compared to a control solution formulation. The study demonstrates that hydrated proniosomes can prolong systemic drug exposure over 3 days and provide a sustained therapeutic effect. The developed proniosomes represent a novel approach to treat acute pain and inflammation with the potential to be administered as a single intravenous dose by a clinician at the time of injury or surgery that provides adequate relief for several days and reduces fluctuations in therapy. Similar systems loaded with different drugs have potential for broader application in anesthesia, anti-infective, antiemetic, and cancer therapy.
Publisher: American Chemical Society (ACS)
Date: 06-2011
DOI: 10.1021/MP100462D
Abstract: Elevated systemic levels of triglyceride-rich lipoproteins (TRL) are a risk factor for the development of atherosclerosis. In patients with metabolic syndrome (MetS), intestinal TRL overproduction contributes to high systemic TRL levels, and recent studies suggest that systemic changes in MetS such as increases in plasma fatty acids and insulin resistance stimulate intestinal TRL production. The current study has examined whether increases in systemic TRL influence intestinal lipid transport and lipoprotein assembly pathways and evaluates the impact of these changes on the absorption and lymphatic transport of lipids and a model lipophilic drug (halofantrine). Mesenteric lymph-duct or bile-duct cannulated rats were administered IV saline or (14)C-labeled chylomicron (CM) (to increase systemic TRL) and intraduodenal (3)H lipids and drug. Changes to biliary lipid output and lymphatic lipid and drug transport were subsequently examined. Increasing systemic TRL concentrations stimulated a significant increase in lymphatic lipid and drug transport. The increased lipids in lymph were not derived from bile or the intestinal blood supply (fatty acid or IV infused (14)C-CM). Rather, an increase in lymphatic transport of duodenally sourced lipids was evident. Increasing plasma levels of TRL therefore stimulated lipid absorption and lymphatic transport via a positive feedback process. The data also suggest that the changes to intestinal TRL formation that result from raised systemic TRL levels may impact on the absorption of highly lipophilic drugs and therefore the reproducibility of drug treatments.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 25-10-2006
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 2013
Abstract: Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Springer Science and Business Media LLC
Date: 26-02-2020
Publisher: Elsevier BV
Date: 07-2013
DOI: 10.1002/JPS.23597
Publisher: MDPI AG
Date: 18-11-2022
DOI: 10.3390/DATA7110164
Abstract: Although various vaccines are now commercially available, they have not been able to stop the spread of COVID-19 infection completely. An excellent strategy to get safe, effective, and affordable COVID-19 treatments quickly is to repurpose drugs that are already approved for other diseases. The process of developing an accurate and standardized drug repurposing dataset requires considerable resources and expertise due to numerous commercially available drugs that could be potentially used to address the SARS-CoV-2 infection. To address this bottleneck, we created the CoviRx.org platform. CoviRx is a user-friendly interface that allows analysis and filtering of large quantities of data, which is onerous to curate manually for COVID-19 drug repurposing. Through CoviRx, the curated data have been made open source to help combat the ongoing pandemic and encourage users to submit their findings on the drugs they have evaluated, in a uniform format that can be validated and checked for integrity by authenticated volunteers. This article discusses the various features of CoviRx, its design principles, and how its functionality is independent of the data it displays. Thus, in the future, this platform can be extended to include any other disease beyond COVID-19.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.JCONREL.2013.12.031
Abstract: A lipophilic prodrug approach has been used to promote the delivery of a model immunomodulator, mycophenolic acid (MPA), to the lymphatic system after oral administration. Lymphatic transport was employed to facilitate enhanced drug uptake into lymphocytes, as recent studies demonstrate that targeted drug delivery to lymph resident lymphocytes may enhance immunomodulatory effects. Two classes of lymph-directing prodrugs were synthesised. Alkyl chain derivatives (octyl mycophenolate, MPA-C8E octadecyl mycophenolate, MPA-C18E and octadecyl mycophenolamide, MPA-C18AM), to promote passive partitioning into lipids in lymphatic transport pathways, and a triglyceride mimetic prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) to facilitate metabolic integration into triglyceride deacylation-reacylation pathways. Lymphatic transport, lymphocyte uptake and plasma pharmacokinetics were assessed in mesenteric lymph and carotid artery cannulated rats following intraduodenal infusion of lipid-based formulations containing MPA or MPA prodrugs. Patterns of prodrug hydrolysis in rat digestive fluid, and cellular re-esterification in vivo, were evaluated to examine the mechanisms responsible for lymphatic transport. Poor enzyme stability and low absorption appeared to limit lymphatic transport of the alkyl derivatives, although two of the three alkyl chain prodrugs - MPA-C18AM (6-fold) and MPA-C18E (13-fold) still increased lymphatic drug transport when compared to MPA. In contrast, 2-MPA-TG markedly increased lymphatic drug transport (80-fold) and drug concentrations in lymphocytes (103-fold), and this was achieved via biochemical incorporation into triglyceride deacylation-reacylation pathways. The prodrug was hydrolysed rapidly to 2-mycophenoloyl glycerol (2-MPA-MG) in the presence of rat digestive fluid, and 2-MPA-MG was subsequently re-esterified in the enterocyte with oleic acid (most likely originating from the co-administered formulation) prior to accessing the lymphatics and lymphocytes. Importantly, after administration of 2-MPA-TG, the concentrations of free MPA in the mesenteric lymph nodes were significantly enhanced (up to 28 fold) when compared to animals administered equimolar quantities of MPA, suggesting the efficient conversion of the esterified prodrug back to the pharmacologically active parent drug. The data suggest that triglyceride mimetic prodrugs have potential as a means of enhancing immunotherapy via drug targeting to lymphocytes and lymph nodes.
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.EJPS.2019.04.003
Abstract: The simultaneous intake of food and drugs can have a strong impact on drug release, absorption, distribution, metabolism and/or elimination and consequently, on the efficacy and safety of pharmacotherapy. As such, food-drug interactions are one of the main challenges in oral drug administration. Whereas pharmacokinetic (PK) food-drug interactions can have a variety of causes, pharmacodynamic (PD) food-drug interactions occur due to specific pharmacological interactions between a drug and particular drinks or food. In recent years, extensive efforts were made to elucidate the mechanisms that drive pharmacokinetic food-drug interactions. Their occurrence depends mainly on the properties of the drug substance, the formulation and a multitude of physiological factors. Every intake of food or drink changes the physiological conditions in the human gastrointestinal tract. Therefore, a precise understanding of how different foods and drinks affect the processes of drug absorption, distribution, metabolism and/or elimination as well as formulation performance is important in order to be able to predict and avoid such interactions. Furthermore, it must be considered that beverages such as milk, grapefruit juice and alcohol can also lead to specific food-drug interactions. In this regard, the growing use of food supplements and functional food requires urgent attention in oral pharmacotherapy. Recently, a new consortium in Understanding Gastrointestinal Absorption-related Processes (UNGAP) was established through COST, a funding organisation of the European Union supporting translational research across Europe. In this review of the UNGAP Working group "Food-Drug Interface", the different mechanisms that can lead to pharmacokinetic food-drug interactions are discussed and summarised from different expert perspectives.
Publisher: American Chemical Society (ACS)
Date: 21-09-2016
DOI: 10.1021/ACS.MOLPHARMACEUT.6B00195
Abstract: In previous studies, a triglyceride (TG) mimetic prodrug of the model immunomodulator mycophenolic acid (MPA) was shown to significantly enhance lymphatic transport of MPA-related species in the rat. The rat gastrointestinal tract, however, is somewhat different from that in higher order species such as dogs and humans and may underestimate lymphatic transport. Here the effectiveness of the prodrug strategy has been examined in conscious greyhound dogs, the GI physiology of which is more representative of that in humans. The bioavailability and lymphatic transport of free MPA and total MPA related materials were examined following oral administration of the parent drug (MPA) and the prodrug (2-MPA-TG) to both thoracic lymph duct cannulated and intact (noncannulated) greyhound dogs. The enrichment of free MPA in lymph nodes and lymph-derived lymphocytes was also determined to examine the efficiency of drug targeting to potential sites of action within the lymph. Via biochemical integration into a series of site-specific metabolic processes, the prodrug markedly increased (288-fold) lymphatic transport of total MPA related material (present as re-esterified 2-MPA-TG) when compared to the parent MPA and the extent of lymphatic transport was significantly greater in the dog (36.4% of the dose recovered in lymph) when compared to the previous data in the rat (13.4% of the dose). Conversion from 2-MPA-TG derivatives to parent MPA occurred in vivo, resulting in a marked increase in MPA concentrations in lymph nodes (5-6-fold) and lymph lymphocytes (21-fold), when compared to animals administered the parent drug. In conclusion, the data demonstrate that the TG prodrug of MPA facilitates efficient delivery of MPA to the lymphatic system in dogs and suggest that the TG prodrug strategy may more effectively facilitate targeted delivery in large animals than in rats.
Publisher: MDPI AG
Date: 06-10-2022
Abstract: SARS-CoV-2 is the cause of the COVID-19 pandemic which has claimed more than 6.5 million lives worldwide, devastating the economy and overwhelming healthcare systems globally. The development of new drug molecules and vaccines has played a critical role in managing the pandemic however, new variants of concern still pose a significant threat as the current vaccines cannot prevent all infections. This situation calls for the collaboration of biomedical scientists and healthcare workers across the world. Repurposing approved drugs is an effective way of fast-tracking new treatments for recently emerged diseases. To this end, we have assembled and curated a database consisting of 7817 compounds from the Compounds Australia Open Drug collection. We developed a set of eight filters based on indicators of efficacy and safety that were applied sequentially to down-select drugs that showed promise for drug repurposing efforts against SARS-CoV-2. Considerable effort was made to evaluate approximately 14,000 assay data points for SARS-CoV-2 FDA/TGA-approved drugs and provide an average activity score for 3539 compounds. The filtering process identified 12 FDA-approved molecules with established safety profiles that have plausible mechanisms for treating COVID-19 disease. The methodology developed in our study provides a template for prioritising drug candidates that can be repurposed for the safe, efficacious, and cost-effective treatment of COVID-19, long COVID, or any other future disease. We present our database in an easy-to-use interactive interface (CoviRx that was also developed to enable the scientific community to access to the data of over 7000 potential drugs and to implement alternative prioritisation and down-selection strategies.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 07-02-2006
Publisher: Elsevier BV
Date: 2021
Publisher: American Chemical Society (ACS)
Date: 13-01-2017
DOI: 10.1021/ACS.MOLPHARMACEUT.6B00792
Abstract: The current studies sought to explore the impact of drug supersaturation and precipitation during the dispersion and digestion of lipid-based formulations (LBFs), on in vivo absorption using a coupled in vitro digestion-in vivo perfusion absorption model. Fenofibrate absorption was evaluated from a number of LBFs with different solubilization and supersaturation capacities, and conditions at the absorptive membrane manipulated by changing perfusion conditions, intestine segment lengths, and by the conduct of experiments in the presence or absence of suspended recipitated drug. LBF dispersion and digestion resulted in varying periods of supersaturation across the different formulations. Even fleeting (5-10 min) periods of supersaturation were able to drive flux across a perfused 10 cm intestinal segment for up to 60 min, although over longer infusion periods (60-80 min) flux dropped in the absence of ongoing drug solubilization and supersaturation. In contrast, the presence or absence of precipitated/suspended drug, had little impact on drug flux. When perfused intestinal segment lengths were extended, the role of initial supersaturation was attenuated and ongoing solubilization conditions became the primary driver of absorptive flux. The data suggest that for highly permeable drugs such as fenofibrate, a short period of supersaturation at the absorptive membrane may be sufficient to drive absorptive drug flux in spite of significant drug precipitation on formulation dispersion or digestion in vitro. In contrast, where longer periods of absorption are required, for ex le, at higher doses, the requirement for ongoing solubilization and supersaturation becomes more apparent.
Publisher: European Respiratory Society (ERS)
Date: 16-04-2021
Publisher: Wiley
Date: 10-02-2022
DOI: 10.1111/MICC.12748
Abstract: Conventionally, in vivo mesenteric lymphatic contractile function is measured using a high magnification transmission microscope (field of view 0.3–1.5 mm), which precludes visualization of extended lengths of vessels embedded in mesenteric fat. Existing software is not optimized for imaging at a low magnification using a contrast agent. We aimed to develop a simple and clinically transferable method for in situ visualization, image analysis, and quantitative assessment of mesenteric lymphatic contractile function over an extended area. Subserosal injection of various blue dyes was taken up by mesenteric lymphatics and visualized under a stereomicroscope (25×), allowing for video recording of 1.4 × 1.1 cm of intact mesentery. A new R package (“vmeasur”) that combines multiple high‐performance image analyses into a single workflow was developed. The edges of each vessel were determined by applying an automated threshold to each frame (with real‐time manual verification). The vessel width at every point in each frame was plotted to provide contractile parameters over time and along the lymphatic vessel length. Contractile parameters and their differences along the length of the vessel were accurately calculated in a rodent model. In a human mesenteric lymphatic, the algorithm was also able to measure changes in diameter over length. This software offers a low cost, rapid, and accessible method to measure lymphatic contractile function over a wide area, showing differences in contractility along the length of a vessel. Because the presence of mesenteric fat has less of an impact on imaging, due to the use of an exogenous contrast agent, there is potential for clinical application.
Publisher: Wiley
Date: 02-08-2016
Publisher: American Chemical Society (ACS)
Date: 13-10-2011
DOI: 10.1021/MP2004862
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.ADDR.2016.04.007
Abstract: Lipid based formulations (LBF) provide well proven opportunities to enhance the oral absorption of drugs and drug candidates that sit close to, or beyond, the boundaries of Lipinski's 'rule-of-five' chemical space. Advantages in permeability, efflux and presystemic metabolism are evident however, the primary benefit is in increases in dissolution and apparent intestinal solubility for lipophilic, poorly water soluble drugs. This review firstly details the inherent advantages of LBF, their general properties and classification, and provides a brief retrospective assessment of the development of LBF over the past fifty years. More detailed analysis of the ability of LBF to promote intestinal solubilisation, supersaturation and absorption is then provided alongside review of the methods employed to assess formulation performance. Critical review of the ability of simple dispersion and more complex in vitro digestion methods to predict formulation performance subsequently reveals marked differences in the correlative ability of in vitro tests, depending on the properties of the drug involved. Notably, for highly permeable low melting drugs e.g. fenofibrate, LBF appear to provide significant benefit in all cases, and sustained ongoing solubilisation may not be required. In other cases, and particularly for higher melting point drugs such as danazol, where re-dissolution of crystalline precipitate drug is likely to be slow, correlations with ongoing solubilisation and supersaturation are more evident. In spite of their potential benefits, one limitation to broader use of LBF is low drug solubility in the excipients employed to generate formulations. Techniques to increase drug lipophilicity and lipid solubility are therefore explored, and in particular those methods that provide for temporary enhancement including lipophilic ionic liquid and prodrug technologies. The transient nature of these lipophilicity increases enhances lipid solubility and LBF viability, but precludes enduring effects on receptor promiscuity and off target toxicity. Finally, recent efforts to generate solid LBF are briefly described as a means to circumvent the need to encapsulate in soft or hard gelatin capsules, although the latter remain popular with consumers and a proven means of LBF delivery.
Publisher: American Chemical Society (ACS)
Date: 25-02-1100
DOI: 10.1021/MP500531E
Abstract: The current study sought to explore whether the subcutaneous administration of lymph targeted dendrimers, conjugated with a model chemotherapeutic (methotrexate, MTX), was able to enhance anticancer activity against lymph node metastases. The lymphatic pharmacokinetics and antitumor activity of PEGylated polylysine dendrimers conjugated to MTX [D-MTX(OH)] via a tumor-labile hexapeptide linker was examined in rats and compared to a similar system where MTX was α-carboxyl O-tert-butylated [D-MTX(OtBu)]. The latter has previously been shown to exhibit longer plasma circulation times. D-MTX(OtBu) was well absorbed from the subcutaneous injection site via the lymph, and 3 to 4%/g of the dose was retained by sentinel lymph nodes. In contrast, D-MTX(OH) showed limited absorption from the subcutaneous injection site, but absorption was almost exclusively via the lymph. The retention of D-MTX(OH) by sentinel lymph nodes was also significantly elevated (approximately 30% dose/g). MTX alone was not absorbed into the lymph. All dendrimers displayed lower lymph node targeting after intravenous administration. Despite significant differences in the lymph node retention of D-MTX(OH) and D-MTX(OtBu) after subcutaneous and intravenous administration, the growth of lymph node metastases was similarly inhibited. In contrast, the administration of MTX alone did not significantly reduce lymph node tumor growth. Subcutaneous administration of drug-conjugated dendrimers therefore provides an opportunity to improve drug deposition in downstream tumor-burdened lymph nodes. In this case, however, increased lymph node biodistribution did not correlate well with antitumor activity, possibly suggesting constrained drug release at the site of action.
Publisher: MDPI AG
Date: 20-09-2022
DOI: 10.20944/PREPRINTS202209.0310.V1
Abstract: SARS-CoV-2, is the cause of the COVID-19 pandemic which has claimed more than six million lives worldwide, devastating the economy and overwhelming healthcare systems globally. The development of new drug molecules and vaccines has played a critical role in managing the pandemic however, new variants of concern still pose a significant threat as the current vaccines cannot prevent all infections. This situation calls for the collaboration of biomedical scientists and healthcare workers across the world. Repurposing approved drugs is an effective way of fast-tracking new treatments for recently emerged diseases. To this end, we have assembled and curated a database consisting of 7817 compounds from the Compounds Australia Open Drug collection. We developed a set of eight filters based on indicators of efficacy and safety that were applied sequentially to down-select drugs that showed promise for drug repurposing efforts against SARS-CoV-2. Considerable effort was made to evaluate approximately 14000 assay data points for SARS-CoV-2 FDA/TGA-approved drugs and provide an average activity score for 3539 compounds. The filtering process identified 12 FDA approved molecules with established safety profiles that have a plausible mechanism for treating COVID-19 disease. The methodology developed in our study provides a template for prioritising repurposable drug candidates that are safe, efficacious, and cost-effective for the treatment of COVID-19, long COVID, or any other future disease. We present our database in an easy-to-use interactive interface (CoviRx, www.covirx.org/) that was also developed to enable scientific community to access to the data of over 7000 potential drugs and to implement alternative prioritisation and down-selection strategies.
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.JCONREL.2017.12.031
Abstract: Therapeutic proteins can facilitate the targeting and treatment of lymphatic diseases (such as cancer metastases, infections and inflammatory diseases) since they are cleared via the lymphatics following interstitial (SC or IM) administration. However, therapeutic proteins are often administered intravenously (IV). Recently therapeutic proteins have been found to access the thoracic lymph in surprisingly high quantities after IV administration. The aim of this study was to determine, for the first time, the major sites of thoracic lymph access of therapeutic proteins, and the protein properties that enhance lymph access, after IV administration. In order to achieve this, novel methods were developed or optimized to collect hepatic, mesenteric or thoracic lymph from male SD rats. Four different sized PEGylated or non-PEGylated therapeutic proteins (native interferon α2b (IFN, 19kDa), PEGylated interferon α2b (IFN-PEG12, 31kDa), PEGylated interferon α2a (IFN-PEG40, 60kDa) or trastuzumab (150kDa)) were then administered via short IV infusion, and plasma and lymph concentrations of the proteins determined via ELISA. The recovery of the therapeutic proteins in the thoracic lymph duct, which collects lymph from most of the body, was significantly greater for trastuzumab, IFN-PEG40 and IFN-PEG12 (all >3% dose over 8h) when compared to native IFN (0.9% dose). Conversely, the thoracic lymph lasma (L/P) concentration ratio and thus efficiency of extravasation and transport through the interstitium to lymph was highest for the smaller proteins IFN and IFN-PEG12 (at 90-100% vs 15-30% for trastuzumab and IFN-PEG40). The lower total recovery of IFN and IFN-PEG12 in thoracic lymph reflected more rapid systemic clearance and thus lower systemic exposure. For all therapeutic proteins, the majority (>80%) of lymph access occurred via the hepatic and mesenteric lymphatics. This lymphatic distribution pattern was supported by quantitative imaging of the lymph node distribution of IV administered Cy5 labelled trastuzumab. Optimizing the properties of IV administered therapeutic proteins represents a viable approach to better target and treat pathological states involving the lymphatics, particularly in the liver and mesentery. This includes cancer metastases, infections and inflammatory diseases. Successful development of the novel technique to collect hepatic lymph will also enable future work to evaluate tissue-specific lymph transport in health and disease.
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1002/JPS.24670
Abstract: The triglyceride (TG) mimetic prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) biochemically integrates into intestinal lipid transport and lipoprotein assembly pathways and thereby promotes the delivery of mycophenolic acid (MPA) into the lymphatic system. As lipoprotein (LP) formation occurs constitutively, even in the fasted state, the current study aimed to determine whether lymphatic transport of 2-MPA-TG was dependent on coadministered exogenous lipid. In vitro incubation of the prodrug with rat digestive fluid and in situ intestinal perfusion experiments revealed that hydrolysis and absorption of the prodrug were relatively unaffected by the quantity of lipid in formulations. In vivo studies in rats, however, showed that the lymphatic transport of TG and 2-MPA-TG was significantly higher following administration with higher quantities of lipid and that oleic acid (C18:1) was more effective in promoting prodrug transport than lipids with higher degrees of unsaturation. The recovery of 2-MPA-TG and TG in lymph correlated strongly (R(2) = 0.99) and more than 97% of the prodrug was associated with chylomicrons. Inhibition of LP assembly by Pluronic L81 simultaneously inhibited the lymphatic transport of 2-MPA-TG and TG. In conclusion, although the TG mimetic prodrug effectively incorporates into TG resynthetic pathways, lipid coadministration is still required to support efficient lymphatic transport.
Publisher: Springer Science and Business Media LLC
Date: 21-06-2013
DOI: 10.1007/S11095-013-1104-6
Abstract: To evaluate the potential for the acidic intestinal unstirred water layer (UWL) to induce drug supersaturation and enhance drug absorption from intestinal mixed micelles, via the promotion of fatty acid absorption. Using a single-pass rat jejunal perfusion model, the absorptive-flux of cinnarizine and (3)H-oleic acid from oleic acid-containing intestinal mixed micelles was assessed under normal acidic microclimate conditions and conditions where the acidic microclimate was attenuated via the co-administration of amiloride. As a control, the absorptive-flux of cinnarizine from micelles of Brij® 97 (a non-ionizable, non-absorbable surfactant) was assessed in the absence and presence of amiloride. Cinnarizine solubility was evaluated under conditions of decreasing pH and decreasing micellar lipid content to assess likely changes in solubilization and thermodynamic activity during micellar passage across the UWL. In the presence of amiloride, the absorptive-flux of cinnarizine and (3)H-oleic acid from mixed micelles decreased 6.5-fold and 3.0-fold, respectively. In contrast, the absorptive-flux of cinnarizine from Brij® 97 micelles remained unchanged by amiloride, and was significantly lower than from the long-chain micelles. Cinnarizine solubility in long-chain micelles decreased under conditions where pH and micellar lipid content decreased simultaneously. The acidic microclimate of the intestinal UWL promotes drug absorption from intestinal mixed micelles via the promotion of fatty acid absorption which subsequently stimulates drug supersaturation. The observations suggest that formulations (or food) containing absorbable lipids (or their digestive precursors) may outperform formulations that lack absorbable components since the latter do not benefit from lipid absorption-induced drug supersaturation.
Publisher: American Medical Association (AMA)
Date: 06-2022
Publisher: Springer Science and Business Media LLC
Date: 21-02-2013
Publisher: Springer Science and Business Media LLC
Date: 12-03-2009
DOI: 10.1007/S11095-009-9860-Z
Abstract: To examine the effect of food on the oral bioavailability of a highly lipophilic, cannabinoid receptor agonist (CRA13) and to explore the basis for the food effect in lymph-cannulated and non-cannulated dogs. Oral bioavailability was assessed in fasted and fed human volunteers and in lymph-cannulated dogs. In fasted dogs, the extent of absorption and oral bioavailability was also examined following administration of radiolabelled CRA13. Food had a substantial positive effect on the oral bioavailability of CRA13 in human volunteers (4.3-4.9 fold increase in AUC(0 - infinity)) and in dogs. The absolute bioavailability of parent drug was low in fasted dogs (8-20%), in spite of good absorption (72-75% of radiolabelled CRA13 recovered in the systemic circulation). In post-prandial lymph-cannulated dogs, bioavailability increased to 47.5% and the majority (43.7%) of the dose was absorbed via the intestinal lymphatic system. The positive food effect for CRA13 does not appear to result from increased post-prandial absorption. Rather these data provide one of the first ex les of a significant increase in bioavailability for a highly lipophilic drug, which is stimulated via almost complete post-prandial transport into the lymph, in turn resulting in a reduction in first-pass metabolism.
Publisher: Wiley
Date: 08-09-2007
DOI: 10.1111/J.1463-1326.2006.00649.X
Abstract: To observe the effect of constant positive airway pressure (CPAP) therapy on regional lipid deposition, muscle metabolism and glucose homeostasis in obese patients with obstructive sleep apnoea syndrome (OSAS). A total of 29 obese patients underwent assessment before and after a minimum of 12-week CPAP therapy. Abdominal adipose tissue was assessed using magnetic resonance imaging. Intramyocellular lipid (IMCL) and skeletal muscle creatine were assessed using (1)H-magnetic resonance spectroscopy. Fasting venous and arterial blood were collected. Glucose control was assessed using the homeostatic model. A subgroup of six patients were also evaluated for skeletal muscle pH, phosphocreatine (PCr) and mitochondrial function using (31)P-magnetic resonance spectroscopy. The s le was ided according to CPAP therapy, with regular users defined as a minimum nightly use of >or=4 h 19 subjects were regular and 10 were irregular CPAP users. Visceral adipose tissue volume and circulating leptin were reduced with regular CPAP use but not with irregular CPAP use. Regular CPAP use also produced an increase in skeletal muscle creatine and resting PCr and a decrease in muscle pH. Neither the regular nor irregular CPAP users showed any change in IMCL content, insulin sensitivity scores or mitochondrial function. These data show that regular CPAP therapy reduces visceral adipose tissue and leptin and improves skeletal muscle metabolites. In obese patients with severe OSAS, regular CPAP use does not improve glucose control, suggesting that the influence of obesity on glucose control dominates over any potential effect of OSAS.
Publisher: Wiley
Date: 21-10-2016
Publisher: Frontiers Media SA
Date: 02-09-2022
Publisher: Elsevier BV
Date: 04-2021
Publisher: Springer Science and Business Media LLC
Date: 21-07-2006
Publisher: Springer Science and Business Media LLC
Date: 31-08-2021
DOI: 10.1007/S11095-021-03093-X
Abstract: Lipophilic conjugates (LCs) of small molecule drugs have been used widely in clinical and pre-clinical studies to achieve a number of pharmacokinetic and therapeutic benefits. For ex le, lipophilic derivatives of drugs are employed in several long acting injectable products to provide sustained drug exposure for hormone replacement therapy and to treat conditions such as neuropsychiatric diseases. LCs can also be used to modulate drug metabolism, and to enhance drug permeation across membranes, either by increasing lipophilicity to enhance passive diffusion or by increasing protein-mediated active transport. Furthermore, such conjugation strategies have been employed to promote drug association with endogenous macromolecular carriers (e.g. albumin and lipoproteins), and this in turn results in altered drug distribution and pharmacokinetic profiles, where the changes can be 'general' (e.g. prolonged plasma half-life) or 'specific' (e.g. enhanced delivery to specific tissues in parallel with the macromolecular carriers). Another utility of LCs is to enhance the encapsulation of drugs within engineered nanoscale drug delivery systems, in order to best take advantage of the targeting and pharmacokinetic benefits of nanomedicines. The current review provides a summary of the mechanisms by which lipophilic conjugates, including in combination with delivery vehicles, can be used to control drug delivery, distribution and therapeutic profiles. The article is structured into sections which highlight a specific benefit of LCs and then demonstrate this benefit with case studies. The review attempts to provide a toolbox to assist researchers to design and optimise drug candidates, including consideration of drug-formulation compatibility.
Publisher: American Physiological Society
Date: 04-2020
Abstract: Recently, peripheral lymphatic vessels were found to transport high-density lipoprotein (HDL) from interstitial tissues to the blood circulation during reverse cholesterol transport. This function is thought to be critical to the clearance of cholesterol from atherosclerotic plaques. The role of organ-specific lymphatics in modulating HDL transport and composition is, however, incompletely understood. This study aimed to 1) determine the contribution of the lymphatics draining the intestine and liver (which are major sites of HDL synthesis) to total (thoracic) lymph HDL transport and 2) verify whether the HDLs in lymph are derived from specific organs and are modified during trafficking in lymph. The mesenteric, hepatic, or thoracic lymph duct was cannulated in nonfasted Sprague-Dawley rats, and lymph was collected over 5 h under anesthesia. Whole lymph and specific lymph lipoproteins (isolated by ultracentrifugation) were analyzed for protein and lipid composition. The majority of thoracic lymph fluid, protein, and lipid mass was sourced from the mesenteric, and to a lesser extent, hepatic lymph. Mesenteric and thoracic lymph were both rich in chylomicrons and very low-density lipoprotein, whereas hepatic lymph and plasma were HDL-rich. The protein and lipid mass in thoracic lymph HDL was mostly sourced from mesenteric lymph, whereas the cholesterol mass was equally sourced from mesenteric and hepatic lymph. HDLs were compositionally distinct across the lymph sources and plasma. The composition of HDL also appeared to be modified during passage from the mesenteric and hepatic to the thoracic lymph duct. Overall, this study demonstrates that the lipoproteins in lymph are organ specific in composition, and the intestine and liver appear to be the main source of HDL in the lymph. NEW & NOTEWORTHY High-density lipoprotein in lymph are organ-specific in composition and derive mostly from the intestine and liver. High-density lipoprotein also appears to be remodeled during transport through the lymphatics. These findings have implications to cardiometabolic diseases that involve perturbations in lipoprotein distribution and metabolism.
Publisher: Springer Science and Business Media LLC
Date: 16-08-2005
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.JCONREL.2021.12.003
Abstract: Challenges to effective delivery of drugs following oral administration has attracted growing interest over recent decades. Small molecule drugs ( 5) and high long-chain triglyceride solubility (> 50 mg/g), properties required to enable drug association with the lipoprotein transport pathway. The majority of small molecule drugs, however, are not this lipophilic and therefore not substantially transported via the intestinal lymph. This has contributed to a growing body of investigation into prodrug approaches to deliver drugs to the lymphatic system by chemical manipulation. Optimised lipophilic prodrugs have the potential to increase lymphatic transport thereby improving oral pharmacokinetics via a reduction in first pass metabolism and may also target of disease-specific reservoirs within the lymphatics. This may provide advantages for current pharmacotherapy approaches for a wide array of pathological conditions, e.g. immune disease, cancer and metabolic disease, and also presents a promising approach for advanced vaccination strategies. In this review, specific emphasis is placed on medicinal chemistry strategies that have been successfully employed to design lipophilic prodrugs to deliberately enable lymphatic transport. Recent progress and opportunities in medicinal chemistry and drug delivery that enable new platforms for efficacious and safe delivery of drugs are critically evaluated.
Publisher: American Chemical Society (ACS)
Date: 30-03-2023
Publisher: Springer Science and Business Media LLC
Date: 26-10-2013
Publisher: Springer Science and Business Media LLC
Date: 27-04-2011
DOI: 10.1007/S11095-011-0446-1
Abstract: Several poorly water-soluble drugs have previously been shown to bind to intestinal (I-FABP) and liver fatty acid binding protein (L-FABP) in vitro. The purpose of this study was to examine the potential role of drug binding to FABPs on intestinal permeability and gut wall metabolism in vivo. The intestinal permeability of ibuprofen, progesterone and midazolam (which bind FABPs) and propranolol (which does not) was examined using an autoperfused recirculating permeability model in control rats and rats where FABP levels were upregulated via pre-feeding a fat-rich diet. The intestinal permeability of drugs which bind FABPs in vitro was increased in animals where FABP levels were upregulated by prefeeding a high fat diet. The gut wall metabolism of midazolam was also reduced in animals with elevated FABP levels. Consistent with their role in the cellular transport of endogenous lipophilic substrates, FABPs appear to facilitate the intracellular disposition of drug molecules that bind FABPs in vitro. Drug binding to FABPs in the enterocyte may also attenuate gut wall metabolism in a manner analogous to the reduction in hepatic extraction mediated by drug binding to plasma proteins in the systemic circulation.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Elsevier BV
Date: 2020
Publisher: Wiley
Date: 20-10-2016
Publisher: Springer Science and Business Media LLC
Date: 06-2020
Publisher: American Chemical Society (ACS)
Date: 16-06-2020
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.IJPHARM.2019.118456
Abstract: The interest in approaches to deliver therapeutics to the lymphatic system has increased in recent years as the lymphatics have been discovered to play an important role in a range of disease states such as cancer metastases, inflammatory and metabolic disease, and acute and critical illness. Therapeutic delivery to lymph has the potential to enhance treatment of these conditions. Currently much of the existing data explores therapeutic delivery to the lymphatic vessels and nodes that drain peripheral tissues and the intestine. Relatively little focus has been given to understanding the anatomy, function and therapeutic delivery to the peritoneal lymphatics. Gaining a better understanding of peritoneal lymphatic structure and function would contribute to the understanding of disease processes involving these lymphatics and facilitate the development of delivery systems to target therapeutics to the peritoneal lymphatics. This review explores the basic anatomy and ultrastructure of the peritoneal lymphatics system, the lymphatic drainage pathways from the peritoneum, and therapeutic and delivery system characteristics (size, lipophilicity and surface properties) that favour lymph uptake and retention after intraperitoneal delivery. Finally, techniques that can be used to quantify uptake into peritoneal lymph are outlined, providing a platform for future studies.
Publisher: Springer Science and Business Media LLC
Date: 20-09-2021
DOI: 10.1038/S42255-021-00457-W
Abstract: Visceral adipose tissue (VAT) encases mesenteric lymphatic vessels and lymph nodes through which lymph is transported from the intestine and mesentery. Whether mesenteric lymphatics contribute to adipose tissue inflammation and metabolism and insulin resistance is unclear. Here we show that obesity is associated with profound and progressive dysfunction of the mesenteric lymphatic system in mice and humans. We find that lymph from mice and humans consuming a high-fat diet (HFD) stimulates lymphatic vessel growth, leading to the formation of highly branched mesenteric lymphatic vessels that 'leak' HFD-lymph into VAT and, thereby, promote insulin resistance. Mesenteric lymphatic dysfunction is regulated by cyclooxygenase (COX)-2 and vascular endothelial growth factor (VEGF)-C-VEGF receptor (R)3 signalling. Lymph-targeted inhibition of COX-2 using a glyceride prodrug approach reverses mesenteric lymphatic dysfunction, visceral obesity and inflammation and restores glycaemic control in mice. Targeting obesity-associated mesenteric lymphatic dysfunction thus represents a potential therapeutic option to treat metabolic disease.
Publisher: Springer Science and Business Media LLC
Date: 24-12-2015
DOI: 10.1007/S11095-015-1843-7
Abstract: In vitro lipid digestion models are commonly used to screen lipid-based formulations (LBF), but in vitro-in vivo correlations are in some cases unsuccessful. Here we enhance the scope of the lipid digestion test by incorporating an absorption 'sink' into the experimental model. An in vitro model of lipid digestion was coupled directly to a single pass in situ intestinal perfusion experiment in an anaesthetised rat. The model allowed simultaneous real-time analysis of the digestion and absorption of LBFs of fenofibrate and was employed to evaluate the influence of formulation digestion, supersaturation and precipitation on drug absorption. Formulations containing higher quantities of co-solvent and surfactant resulted in higher supersaturation and more rapid drug precipitation in vitro when compared to those containing higher quantities of lipid. In contrast, when the same formulations were examined using the coupled in vitro lipid digestion - in vivo absorption model, drug flux into the mesenteric vein was similar regardless of in vitro formulation performance. For some drugs, simple in vitro lipid digestion models may underestimate the potential for absorption from LBFs. Consistent with recent in vivo studies, drug absorption for rapidly absorbed drugs such as fenofibrate may occur even when drug precipitation is apparent during in vitro digestion.
Publisher: Springer Science and Business Media LLC
Date: 16-10-2015
DOI: 10.1038/NRD4608
Abstract: The lymphatic system serves an integral role in fluid homeostasis, lipid metabolism and immune control. In cancer, the lymph nodes that drain solid tumours are a primary site of metastasis, and recent studies have suggested intrinsic links between lymphatic function, lipid deposition, obesity and atherosclerosis. Advances in the current understanding of the role of the lymphatics in pathological change and immunity have driven the recognition that lymph-targeted delivery has the potential to transform disease treatment and vaccination. In addition, the design of lymphatic delivery systems has progressed from simple systems that rely on passive lymphatic access to sophisticated structures that use nanotechnology to mimic endogenous macromolecules and lipid conjugates that 'hitchhike' onto lipid transport processes. Here, we briefly summarize the lymphatic system in health and disease and the varying mechanisms of lymphatic entry and transport, as well as discussing ex les of lymphatic delivery that have enhanced therapeutic utility. We also outline future challenges to effective lymph-directed therapy.
Publisher: Springer Science and Business Media LLC
Date: 04-07-2013
DOI: 10.1007/S11095-013-1126-0
Abstract: Drugs with low aqueous solubility commonly show low and erratic absorption after oral administration. Myriad approaches have therefore been developed to promote drug solubilization in the gastrointestinal (GI) fluids. Here, we offer insight into the unique manner by which lipid-based formulations (LBFs) may enhance the absorption of poorly water-soluble drugs via co-stimulation of solubilization and supersaturation. Supersaturation provides an opportunity to generate drug concentrations in the GI tract that are in excess of the equilibrium crystalline solubility and therefore higher than that achievable with traditional formulations. Incorporation of LBF into lipid digestion and absorption pathways provides multiple drivers of supersaturation generation and the potential to enhance thermodynamic activity and absorption. These drivers include 1) formulation dispersion, 2) lipid digestion, 3) interaction with bile and 4) lipid absorption. However, high supersaturation ratios may also stimulate drug precipitation and reduce exposure where re-dissolution limits absorption. The most effective formulations are likely to be those that generate moderate supersaturation and do so close to the site of absorption. LBFs are particularly well suited to these criteria since solubilization protects against high supersaturation ratios, and supersaturation initiation typically occurs in the small intestine, at the absorptive membrane.
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1002/JPS.23211
Publisher: Elsevier BV
Date: 03-2008
Publisher: American Chemical Society (ACS)
Date: 22-03-2023
Publisher: MDPI AG
Date: 21-09-2022
DOI: 10.20944/PREPRINTS202209.0323.V1
Abstract: Although various vaccines are now commercially available, they have not been able to stop the spread of COVID-19 infection completely. An excellent strategy to quickly get safe, effective, and affordable COVID-19 treatment is to repurpose drugs that are already approved for other diseases as adjuvants along with the ongoing vaccine regime. The process of developing an accurate and standardized drug repurposing dataset requires a considerable level of resources and expertise due to the commercial availability of an extensive array of drugs that could be potentially used to address the SARS-CoV-2 infection. To address this bottleneck, we created the CoviRx platform. CoviRx is a user-friendly interface that provides access to the data, which is manually curated for COVID-19 drug repurposing data. Through CoviRx, the data curated has been made open-source to help advance drug repurposing research. CoviRx also encourages users to submit their findings after thoroughly validating the data, followed by merging it by enforcing uniformity and integ-rity-preserving constraints. This article discusses the various features of CoviRx and its design principles. CoviRx has been designed so that its functionality is independent of the data it dis-plays. Thus, in the future, this platform can be extended to include any other disease X beyond COVID-19. CoviRx can be accessed at www.covirx.org.
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.JCONREL.2019.01.002
Abstract: Lymphocytes play a central role in the pathology of a range of chronic conditions such as autoimmune disease, transplant rejection, leukemia, lymphoma HIV/AIDs and cardiometabolic diseases such as atherosclerosis. Current treatments for lymphocyte-associated conditions are incompletely effective and/or complicated by a range of off-target toxicities. One major challenge is poor drug access to lymphocytes via the systemic blood and this may be attributed, at least in part, to the fact that lymphocytes are concentrated within lymph fluid and lymphoid tissues, particularly in gut-associated lymphatics. Here we demonstrate that promoting drug uptake into the intestinal lymphatics with a long chain fatty acid, thereby increasing lymphocyte access, enhances the pharmacodynamic effect of a highly lipophilic liver X receptor (LXR) agonist, WAY-252623, that has been suggested as a potential treatment for atherosclerosis. This has been exemplified by: (1) increased mRNA expression of key markers of LXR activation (ABCA1) and regulatory T cells (Foxp3) in local lymphatic lymphocytes and (2) enhanced numbers of CD4
Publisher: Elsevier BV
Date: 11-2014
DOI: 10.1016/J.EJPB.2014.08.006
Abstract: The present study investigated the use of lipid based drug delivery systems to enhance the oral bioavailability of the CETP inhibitors CP-532,623 and torcetrapib. A series of self-emulsifying lipid based drug delivery systems (SEDDS) were assembled and examined using an in vitro lipid digestion model to evaluate patterns of drug precipitation under simulated intestinal conditions. Drug exposure after oral administration of the same formulations was subsequently assessed in beagle dogs. CP-532,623 was maintained in a solubilised state during dispersion of most formulations in simulated intestinal fluid, however, solubilisation capacity was reduced to various degrees upon in vitro digestion. Administration of SEDDS formulations to beagle dogs resulted in moderate differences in plasma AUC when compared to the differences in solubilisation observed in vitro. Similar trends were observed for torcetrapib. In all cases, however, in vivo exposure of CP-532,623 was greatly enhanced by administration in lipid based drug delivery systems when compared to a powder formulation. Some correlation between in vitro solubilisation and in vivo drug exposure (AUC) was evident however, this was not linear. The data suggest that for highly lipophilic drugs such as CP-532,623 in vitro digestion data may be a conservative in vitro indicator of utility and that good exposure may be evident even for formulations that result in significant drug precipitation during in vitro digestion.
Publisher: American Chemical Society (ACS)
Date: 12-11-2010
DOI: 10.1021/MP100259A
Publisher: Frontiers Media SA
Date: 21-05-2020
Publisher: American Chemical Society (ACS)
Date: 18-10-2019
DOI: 10.1021/ACS.MOLPHARMACEUT.9B00855
Abstract: Drugs are commonly administered via the intraperitoneal (IP) route to treat localized infections and cancers in patients and to test drug efficacy and toxicity in preclinical studies. Despite this, there remain large gaps in our understanding of drug absorption routes (lymph vs blood) and pharmacokinetics following IP administration. This is particularly true when drugs are administered in complex delivery systems such as liposomes which are the main marketed formulation for several drugs that are administered intraperitoneally. This study investigated the impact of liposome surface properties (charge and PEGylation) on absorption into lymph and blood, and lymphatic disposition patterns, following IP administration. To achieve this, stable
Start Date: 07-2023
End Date: 06-2026
Amount: $615,316.00
Funder: Australian Research Council
View Funded ActivityStart Date: 05-2021
End Date: 05-2024
Amount: $676,622.00
Funder: Australian Research Council
View Funded ActivityStart Date: 01-2023
End Date: 01-2026
Amount: $711,535.00
Funder: Australian Research Council
View Funded ActivityStart Date: 04-2022
End Date: 03-2025
Amount: $436,908.00
Funder: Australian Research Council
View Funded Activity