Validation of cell-based OATP1B1 assays to assess drug transport and the potential for drug-drug interaction to support regulatory submissions

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
P SharmaDominic Surry

Abstract

Transporters are carrier proteins that may influence pharmacokinetic, pharmacodynamic, and toxicological characteristics of drugs. The development of validated in vitro transporter models is imperative to support regulatory submissions of drug candidates. This study is focused on utilizing human embryonic kidney (HEK) 293 cell cultures genetically transfected with the human organic anion transporting polypeptides (OATP) 1B1 transporter to identify substrates and inhibitors in drug development. The kinetics of OATP1B1-mediated uptake of [(3)H]-oestradiol 17beta-glucuronide and inhibition of uptake by rifamycin SV were used to determine K(m), V(max), and IC(50) values over a range of passage numbers to investigate accuracy and precision. The mean K(m) and V(max) values were found to be 6.3 +/- 1.2 microM and 460 +/- 96 pmol min(-1) mg(-1), respectively. The mean IC(50) value for rifamycin SV was 0.23 +/- 0.07 microM on uptake of 1 microM [(3)H]-oestradiol 17beta-glucuronide. These data were similar to previously reported values (accuracy greater than 82%), reproducible (precision less than 29%) and exhibited low standard deviations (SDs) obviating the need to study test compounds on more than one occasion. [(3)H]-oestrone 3-sulfa...Continue Reading

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Oct 30, 2015·Expert Opinion on Drug Discovery·Donna A Volpe
Apr 28, 2012·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Pradeep SharmaDominic Surry
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Mar 6, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Elizabeth R HaydenJason A Sprowl

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