The Development, Characterization, and Application of an OATP1B1 Inhibition Assay in Drug Discovery

Soars, Matthew G.; Barton, Patrick; Ismair, Manfred G.; Jupp, Rachael; Riley, Robert J.

doi:10.1124/dmd.111.042382

Cited by 31 publications

(31 citation statements)

References 43 publications

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“…The second best model is obtained by incorporation of predicted OATP1B3 inhibition, with predicted OATP2B1 inhibition resulting in the least accurate model (RT (3)). This may indicate a more significant role for OATP1B1 in biliary excretion of compounds than OATP1B3 or OATP2B1, which is in agreement with the literature that highlight mainly the role of OATP1B1 subfamily in the elimination of compounds (Soars et al, 2012). Moreover, OATP1B1 is known to have a higher expression level than the other two proteins in the sinusoidal membrane of hepatocytes (Tu et al, 2013).…”

Section: Effect Of Oatp Binding On Biliary Excretion Modelssupporting

confidence: 91%

“…Among transporter proteins, OATPs have been suggested as some of the major contributors to the uptake of compounds by hepatocytes and biliary excretion of compounds (Fenner et al, 2012). Recently, OATP1B1 inhibition measures have been suggested as a suitable surrogate for the more complicated human hepatic uptake assays (Soars et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…In comparison with OATP1B subfamily (Chang et al, 2005;De Bruyn et al, 2013;Soars et al, 2012), very little is known about OATP2B1 ligands with only few literature data available and no in silico results (Karlgren et al, 2012a). The structure of OATP2B1 has been shown to be very similar to OATP1B3 using in silico homology modeling studies (Meier-abt et al, 2005).…”

Section: Oatp2b1 Inhibitorsmentioning

confidence: 99%

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Effect of OATP-binding on the prediction of biliary excretion

Sharifi

Ghafourian

2016

Xenobiotica

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Article (Accepted Version) http://sro.sussex.ac.uk Sharifi, Mohsen and Ghafourian, Taravat (2017) Effect of OATP-binding on the prediction of biliary excretion. Xenobiotica, 47 (7). pp. [614][615][616][617][618][619][620][621][622][623][624][625][626][627][628][629][630][631] This version is available from Sussex Research Online: http://sro.sussex.ac.uk/64120/ This document is made available in accordance with publisher policies and may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the URL above for details on accessing the published version. Copyright and reuse:Sussex Research Online is a digital repository of the research output of the University.Copyright and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable, the material made available in SRO has been checked for eligibility before being made available.Copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. The results indicated that incorporation of predicted OATP inhibition improves accuracy of biliary excretion models. The best result was obtained from a simple regression tree that used predicted OATP1B1 percentage inhibition at the root node of the tree. Effect of OATP-binding on the prediction of biliary excretion

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Section: Effect Of Oatp Binding On Biliary Excretion Modelssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Oatp2b1 Inhibitorsmentioning

confidence: 99%

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Effect of OATP-binding on the prediction of biliary excretion

Sharifi

Ghafourian

2016

Xenobiotica

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“…Transporter-mediated DDIs were predicted for a set of clinical inhibitors with different isoform specificity using in vitro inhibitory data. Because OATP inhibition is substrate-dependent (e.g., Noe et al, 2007;Soars et al, 2012), the in vitro inhibitory capacity was determined with atorvastatin as the victim drug. There were clear differences in OATP inhibition pattern when using atorvastatin as substrate instead of prototypical model substrates (Table 4).…”

Section: Discussionmentioning

confidence: 99%

Hepatic Uptake of Atorvastatin: Influence of Variability in Transporter Expression on Uptake Clearance and Drug-Drug Interactions

et al. 2014

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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 (CL upt ) is not yet clarified. To elucidate this issue, we investigated the relative contribution of NTCP, OATP1B1, OATP1B3, and OATP2B1 to atorvastatin CL upt in 12 human liver samples. The impact of inhibition on atorvastatin CL upt 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 CL upt 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 NTCP 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 CL upt 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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“…Currently available in vitro tools increase in complexity from single-gene overexpressing immortalized cell lines to isolated hepatocytes and 3-dimensional cultured hepatocyte systems. Cells expressing individual uptake transporters have been extensively used to determine if a test compound is an inhibitor of a transporter and/or a substrate (Sharma et al, 2012;Soars et al, 2012;Varma et al, 2012a). The studies are readily amenable for obtaining various kinetic parameters, including K M , V max , and IC 50 of substrates or inhibitors.…”

Section: Predicting Clearancementioning

confidence: 99%

A Perspective on the Prediction of Drug Pharmacokinetics and Disposition in Drug Research and Development

Feng

Goosen

et al. 2013

Drug Metab Dispos

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Prediction of human pharmacokinetics of new drugs, as well as other disposition attributes, has become a routine practice in drug research and development. Prior to the 1990s, drug disposition science was used in a mostly descriptive manner in the drug development phase. With the advent of in vitro methods and availability of human-derived reagents for in vitro studies, drugdisposition scientists became engaged in the compound design phase of drug discovery to optimize and predict human disposition properties prior to nomination of candidate compounds into the drug development phase. This has reaped benefits in that the attrition rate of new drug candidates in drug development for reasons of unacceptable pharmacokinetics has greatly decreased. Attributes that are predicted include clearance, volume of distribution, halflife, absorption, and drug-drug interactions. In this article, we offer our experience-based perspectives on the tools and methods of predicting human drug disposition using in vitro and animal data.

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The Development, Characterization, and Application of an OATP1B1 Inhibition Assay in Drug Discovery

Cited by 31 publications

References 43 publications

Effect of OATP-binding on the prediction of biliary excretion

Effect of OATP-binding on the prediction of biliary excretion

Hepatic Uptake of Atorvastatin: Influence of Variability in Transporter Expression on Uptake Clearance and Drug-Drug Interactions

A Perspective on the Prediction of Drug Pharmacokinetics and Disposition in Drug Research and Development

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