title: In vitro evaluation of hepatic transporter-mediated clinical drug-drug interactions: hepatocyte model optimization and retrospective investigation.
abstract: To assess the feasibility of using sandwich-cultured human hepatocytes (SCHHs) as a model to characterize transport kinetics for in vivo pharmacokinetic prediction, the expression of organic anion-transporting polypeptide (OATP) proteins in SCHHs, along with biliary efflux transporters, was confirmed quantitatively by liquid chromatography-tandem mass spectrometry. Rifamycin SV (Rif SV), which was shown to completely block the function of OATP transporters, was selected as an inhibitor to assess the initial rates of active uptake. The optimized SCHH model was applied in a retrospective investigation of compounds with known clinically significant OATP-mediated uptake and was applied further to explore drug-drug interactions (DDIs). Greater than 50% inhibition of active uptake by Rif SV was found to be associated with clinically significant OATP-mediated DDIs. We propose that the in vitro active uptake value therefore could serve as a cutoff for class 3 and 4 compounds of the Biopharmaceutics Drug Disposition Classification System, which could be integrated into the International Transporter Consortium decision tree recommendations to trigger clinical evaluations for potential DDI risks. Furthermore, the kinetics of in vitro hepatobiliary transport obtained from SCHHs, along with protein expression scaling factors, offer an opportunity to predict complex in vivo processes using mathematical models, such as physiologically based pharmacokinetics models.
authors.affiliation: Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Worldwide Research and Development, Pfizer, Inc., Mailstop 8220-2475, Groton, CT 06340, USA.
authors.forename: Yi-An
authors.initials: YA
authors.lastname: Bi
authors.forename: Emi
authors.initials: E
authors.lastname: Kimoto
authors.forename: Samantha
authors.initials: S
authors.lastname: Sevidal
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Jones
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Barton
authors.forename: Sarah
authors.initials: S
authors.lastname: Kempshall
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Whalen
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Chengjie
authors.initials: C
authors.lastname: Ji
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Fenner
authors.forename: Ayman F
authors.initials: AF
authors.lastname: El-Kattan
authors.forename: Yurong
authors.initials: Y
authors.lastname: Lai
mesh_terms: D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D027361:Organic Anion Transporters / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D012189:Retrospective Studies
chemical_list: D027361:Organic Anion Transporters; D004364:Pharmaceutical Preparations