title: Effect of pregnane X receptor ligands on transport mediated by human OATP1B1 and OATP1B3.
abstract: The pregnane X receptor is a ligand-activated transcription factor that is abundantly expressed in hepatocytes. Numerous drugs are pregnane X receptor ligands. To bind to their receptor they must cross the sinusoidal membrane. Organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) are polyspecific transporters expressed at the sinusoidal membrane of human hepatocytes. They mediate transport of a variety of drugs including the pregnane X receptor ligands rifampicin and dexamethasone. To test whether additional pregnane X receptor ligands interact with OATP1B1- and 1B3-mediated transport, we developed Chinese Hamster Ovary (CHO) cell lines stably expressing OATP1B1 or 1B3 at high levels. OATP1B1- and 1B3-mediated estradiol-17beta-glucuronide uptake was inhibited by several pregnane X receptor ligands in a concentration dependent way. IC(50) values for rifampicin, paclitaxel, mifepristone, and troglitazone were within their respective pharmacological free plasma concentrations. Kinetic analysis revealed that clotrimazole inhibits OATP1B1-mediated estradiol-17beta-glucuronide transport with a K(i) of 7.7+/-0.3 microM in a competitive way. However, uptake of OATP1B3-mediated estradiol-17beta-glucuronide was stimulated and this stimulation was due to an increased apparent affinity. Transport of estrone-3-sulfate was hardly affected while all other substrates tested were inhibited. Additional azoles like fluconazole, ketoconazole and miconazole did not stimulate OATP1B3-mediated estradiol-17beta-glucuronide transport. In summary, these results demonstrate that pregnane X receptor ligands, by inhibiting or stimulating OATP-mediated uptake, can lead to drug-drug interactions at the transporter level.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Chunshan
authors.initials: C
authors.lastname: Gui
authors.forename: Yi
authors.initials: Y
authors.lastname: Miao
authors.forename: Lucas
authors.initials: L
authors.lastname: Thompson
authors.forename: Bret
authors.initials: B
authors.lastname: Wahlgren
authors.forename: Melissa
authors.initials: M
authors.lastname: Mock
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.forename: Bruno
authors.initials: B
authors.lastname: Hagenbuch
mesh_terms: D000818:Animals; D016466:CHO Cells; D002839:Chromans / Q000494:pharmacology; D003022:Clotrimazole / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008024:Ligands; D027381:Liver-Specific Organic Anion Transporter 1; D015735:Mifepristone / Q000494:pharmacology; D027361:Organic Anion Transporters / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000187:drug effects* / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D045162:Thiazolidinediones / Q000494:pharmacology; D014162:Transfection; D000077288:Troglitazone; D015262:Xenobiotics / Q000494:pharmacology*
chemical_list: D002839:Chromans; D008024:Ligands; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D045162:Thiazolidinediones; D015262:Xenobiotics; C025483:estradiol-17 beta-glucuronide; D004970:Estrone; D015735:Mifepristone; D004958:Estradiol; D003022:Clotrimazole; D000077288:Troglitazone; D017239:Paclitaxel; C017296:estrone sulfate; D012293:Rifampin