| 1. |
- Galetin, Aleksandra, et al.
(author)
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Membrane transporters in drug development and as determinants of precision medicine
- 2024
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In: NATURE REVIEWS DRUG DISCOVERY. - 1474-1776 .- 1474-1784.
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Research review (peer-reviewed)abstract
- The effect of membrane transporters on drug disposition, efficacy and safety is now well recognized. Since the initial publication from the International Transporter Consortium, significant progress has been made in understanding the roles and functions of transporters, as well as in the development of tools and models to assess and predict transporter-mediated activity, toxicity and drug-drug interactions (DDIs). Notable advances include an increased understanding of the effects of intrinsic and extrinsic factors on transporter activity, the application of physiologically based pharmacokinetic modelling in predicting transporter-mediated drug disposition, the identification of endogenous biomarkers to assess transporter-mediated DDIs and the determination of the cryogenic electron microscopy structures of SLC and ABC transporters. This article provides an overview of these key developments, highlighting unanswered questions, regulatory considerations and future directions. Significant progress has been made in understanding the influence of membrane transporters in drug disposition and response. Here, the International Transporter Consortium provides an update on the current status of membrane transporters in drug development and regulatory requirements, discusses recent scientific advances in the field and highlights future directions and unanswered questions.
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| 2. |
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| 3. |
- Karlgren, Maria, et al.
(author)
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Classification of Inhibitors of Hepatic Organic Anion Transporting Polypeptides (OATPs) : Influence of Protein Expression on Drug - Drug Interactions
- 2012
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:10, s. 4740-4763
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Journal article (peer-reviewed)abstract
- The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1, The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
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| 4. |
- Pedersen, Jenny M., et al.
(author)
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Biliary Drug Excretion and Drug-drug Interactions in Sandwich Cultured Human Hepatocytes Predicted from Inverted Membrane Vesicles and Targeted Proteomics
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Other publication (other academic/artistic)abstract
- The ABC multidrug resistance proteins in the canalicular membrane are important contributors to the pharmacokinetic properties of drugs and endogenous compounds. In this study, a new approach for determining the individual contribution from three ABC transporters to the biliary clearance was investigated. First, the inhibition of P-glycoprotein (Pgp/ABCB1), Breast Cancer Resistance Protein (BCRP/ABCG2) and Multidrug-Resistance Associated Protein 2 (MRP2/ABCC2) was investigated in inverted membrane vesicles from HEK293 cells overexpressing each of the ABC proteins. Inhibition profiles of prototypic substrate transport were obtained for 24 compounds and compared with results obtained in alternative expression systems. A common substrate for the three transporters was found in estradiol 17β-glucuronide (E17G). The contribution of each transporter to the E17G biliary efflux was investigated in HEK vesicles and in sandwich cultured human hepatocytes (SCHH), using nine inhibitors with different specificity towards each of the ABC-proteins. After quantification of transport kinetics and protein expression, the maximal transport activity (MTA) of each of the transporters was calculated and their contribution to the biliary clearance of E17G was predicted. The results show a good correlation between HEK-MRP2 and Sf9-MRP2 vesicle data. However, up to 40-fold lower IC50-values were obtained for Pgp and BCRP in the HEK vesicles compared to cellular expression systems. The physiologically more relevant SCHH were found to identify ABC inhibitors observed in the vesicle system that lost their ABC inhibition in this more complex model. SCHH therefore contribute with important additional information impossible to assess in vesicular systems. Finally, the MTA and subsequent of biliary clearance determinations were used to predict the absolute biliary excretion of E17G in SCHH, which was predicted with a prediction accuracy of 90%.
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| 5. |
- Prasad, Bhagwat, et al.
(author)
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Toward a Consensus on Applying Quantitative Liquid Chromatography-Tandem Mass Spectrometry Proteomics in Translational Pharmacology Research : A White Paper
- 2019
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In: Clinical Pharmacology and Therapeutics. - : WILEY. - 0009-9236 .- 1532-6535. ; 106:3, s. 525-543
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Journal article (peer-reviewed)abstract
- Quantitative translation of information on drug absorption, disposition, receptor engagement, and drug-drug interactions from bench to bedside requires models informed by physiological parameters that link in vitro studies to in vivo outcomes. To predict in vivo outcomes, biochemical data from experimental systems are routinely scaled using protein quantity in these systems and relevant tissues. Although several laboratories have generated useful quantitative proteomic data using state-of-the-art mass spectrometry, no harmonized guidelines exit for sample analysis and data integration to in vivo translation practices. To address this gap, a workshop was held on September 27 and 28, 2018, in Cambridge, MA, with 100 experts attending from academia, the pharmaceutical industry, and regulators. Various aspects of quantitative proteomics and its applications in translational pharmacology were debated. A summary of discussions and best practices identified by this expert panel are presented in this "White Paper" alongside unresolved issues that were outlined for future debates.
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| 6. |
- Vildhede, Anna, et al.
(author)
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Hepatic Uptake of Atorvastatin : Influence of Variability in Transporter Expression on Uptake Clearance and Drug-Drug Interactions
- 2014
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In: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 42:7, s. 1210-1218
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Journal article (peer-reviewed)abstract
- Differences in the expression and function of the organic anion transporting polypeptide (OATP) transporters contribute to interindividual variability in atorvastatin clearance. However, the importance of the bile acid transporter sodium taurocholate cotransporting polypeptide (NTCP, SLC10A1) in atorvastatin uptake clearance (CLupt) is not yet clarified. To elucidate this issue, we investigated the relative contribution of NTCP, OATP1B1, OATP1B3, and OATP2B1 to atorvastatin CLupt in 12 human liver samples. The impact of inhibition on atorvastatin CLupt was also studied, using inhibitors of different isoform specificities. Expression levels of the four transport proteins were quantified by liquid chromatography tandem mass spectrometry. These data, together with atorvastatin in vitro kinetics, were used to predict the maximal transport activity (MTA) and interindividual differences in CLupt of each transporter in vivo. Subsequently, hepatic uptake impairment on coadministration of five clinically interacting drugs was predicted using in vitro inhibitory potencies. NTCP and OATP protein expression varied 3.7- to 32-fold among the 12 sample donors. The rank order in expression was OATP1B1 > OATP1B3 approximate to NTCP approximate to OATP2B1. NTCP was found to be of minor importance in atorvastatin disposition. Instead, OATP1B1 and OATP1B3 were confirmed as the major atorvastatin uptake transporters. The average contribution to atorvastatin uptake was OATP1B1 > OATP1B3 >> OATP2B1 > NTCP, although this rank order varied among individuals. The interindividual differences in transporter expression and CLupt resulted in marked differences in drug-drug interactions due to isoform-specific inhibition. We conclude that this variation should be considered in in vitro to in vivo extrapolations.
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| 7. |
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| 8. |
- Vildhede, Anna, et al.
(author)
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Mechanistic Modeling of Pitavastatin Disposition in Sandwich-Cultured Human Hepatocytes : A Proteomics-Informed Bottom-Up Approach
- 2016
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In: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 44:4, s. 505-516
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Journal article (peer-reviewed)abstract
- Isolated human hepatocytes are commonly used to predict transporter-mediated clearance in vivo. Such predictions, however, do not provide estimations of transporter contributions and consequently do not allow predictions of the outcome resulting from a change in the activity of a certain transporter, e.g., by inhibition or a genetic variant with reduced function. Pitavastatin is a drug that is heavily dependent on hepatic transporters for its elimination and it is mainly excreted as unchanged drug in the bile. For this reason, pitavastatin was used as a model drug to demonstrate the applicability of a bottom-up approach to predict transporter-mediated disposition in sandwich-cultured human hepatocytes (SCHH), allowing for the estimation of transporter contributions. Transport experiments in transfected HEK293 cells and inverted membrane vesicles overexpressing each of the relevant transport proteins were used to generate parameter estimates for the mechanistic model. By adjusting for differences in transporter abundance between the in vitro systems and individual SCHH batches, the model successfully predicted time profiles of medium and intracellular accumulation. Our predictions of pitavastatin bile accumulation could, however, not be confirmed due to a very low biliary excretion of pitavastatin in relation to the hepatic uptake in our SCHH. This study is, to our knowledge, the first to successfully simulate transporter-mediated processes in a complex system such as SCHH at the level of individual transport proteins using a bottom-up approach.
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