Effect of pregnane X receptor ligands on transport mediated by human OATP1B1 and OATP1B3
| Autor: | Bruno Hagenbuch, Bret Wahlgren, Chunshan Gui, Bruno Stieger, Yi Miao, Melissa Mock, Lucas Thompson |
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| Přispěvatelé: | University of Zurich, Hagenbuch, B |
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Receptors
Steroid Paclitaxel Estrone Organic Anion Transporters 610 Medicine & health CHO Cells Organic Anion Transporters Sodium-Independent Ligands Transfection Article Xenobiotics Solute Carrier Organic Anion Transporter Family Member 1B3 Troglitazone Cricetulus Cricetinae medicine Animals Humans Drug Interactions Chromans Clotrimazole Receptor Pharmacology Pregnane X receptor biology Dose-Response Relationship Drug Estradiol Chemistry Liver-Specific Organic Anion Transporter 1 Chinese hamster ovary cell Pregnane X Receptor Transporter In vitro Organic anion-transporting polypeptide Kinetics Mifepristone medicine.anatomical_structure 3004 Pharmacology Biochemistry Nuclear receptor 10199 Clinic for Clinical Pharmacology and Toxicology Hepatocyte biology.protein Thiazolidinediones Rifampin |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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