title: Preclinical Mouse Models To Study Human OATP1B1- and OATP1B3-Mediated Drug-Drug Interactions in Vivo.
abstract: The impact of OATP drug uptake transporters in drug-drug interactions (DDIs) is increasingly recognized. OATP1B1 and OATP1B3 are human hepatic uptake transporters that can mediate liver uptake of a wide variety of drugs. Recently, we generated transgenic mice with liver-specific expression of human OATP1B1 or OATP1B3 in a mouse Oatp1a/1b knockout background. Here, we investigated the applicability of these mice in OATP-mediated drug-drug interaction studies using the prototypic OATP inhibitor rifampicin and a good OATP substrate, the anticancer drug methotrexate (MTX). We next assessed the possibility of OATP-mediated interactions between telmisartan and MTX, a clinically relevant drug combination. Using HEK293 cells overexpressing OATP1B1 or OATP1B3, we estimated IC50 values for both rifampicin (0.9 or 0.3 μM) and telmisartan (6.7 or 7.9 μM) in inhibiting OATP-mediated MTX uptake in vitro. Using wild-type, Oatp1a/1b-/-, and OATP1B1- or OATP1B3-humanized transgenic mice, we found that rifampicin inhibits hepatic uptake of MTX mediated by the mouse Oatp1a/1b and human OATP1B1 and OATP1B3 transporters at clinically relevant concentrations. This highlights the applicability of these mouse models for DDI studies and may be exploited in the clinic to reduce the dose and thus methotrexate-mediated toxicity. On the other hand, telmisartan inhibited only human OATP1B1-mediated hepatic uptake of MTX at concentrations higher than those used in the clinic; therefore risks for OATP-mediated clinical DDIs for this drug combination are likely to be low. Overall, we show here that OATP1B1- and OATP1B3-humanized mice can be used as in vivo tools to assess and possibly predict clinically relevant DDIs.
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute , Amsterdam, The Netherlands.
authors.forename: Selvi
authors.initials: S
authors.lastname: Durmus
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute , Amsterdam, The Netherlands.|Department of Physiology and Nutrition and Institute of Food Safety Research (INSA-UB), University of Barcelona , Barcelona, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Lozano-Mena
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute , Amsterdam, The Netherlands.
authors.forename: Anita
authors.initials: A
authors.lastname: van Esch
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute , Amsterdam, The Netherlands.
authors.forename: Els
authors.initials: E
authors.lastname: Wagenaar
authors.affiliation: Department of Clinical Chemistry, The Netherlands Cancer Institute , Amsterdam, The Netherlands.
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
authors.affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute , Amsterdam, The Netherlands.
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D001562:Benzimidazoles / Q000378:metabolism; D001565:Benzoates / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology; D004347:Drug Interactions / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D008727:Methotrexate / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D027361:Organic Anion Transporters / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D000077333:Telmisartan
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001565:Benzoates; D027381:Liver-Specific Organic Anion Transporter 1; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D000077333:Telmisartan; D008727:Methotrexate
keywords: DDI; OATP1B1; OATP1B3; drug−drug interactions; hepatic uptake; methotrexate; plasma disposition; rifampicin; telmisartan