Effect of pregnane X receptor ligands on transport mediated by human OATP1B1 and OATP1B3.
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Gui C, Miao Y, Thompson L, Wahlgren B, Mock M, Stieger B, Hagenbuch B
Effect of pregnane X receptor ligands on transport mediated by human OATP1B1 and OATP1B3.
Eur J Pharmacol. 2008 Apr 14;584(1):57-65. doi: 10.1016/j.ejphar.2008.01.042. Epub 2008 Feb 8.
- PubMed ID
- 18321482 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Clotrimazole Solute carrier organic anion transporter family member 1B1 Protein Humans UnknownSubstrateInhibitorDetails Clotrimazole Solute carrier organic anion transporter family member 1B3 Protein Humans UnknownInducerDetails Mifepristone Solute carrier organic anion transporter family member 1B1 Protein Humans NoInhibitorDetails Mifepristone Solute carrier organic anion transporter family member 1B3 Protein Humans NoInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareFluvastatinMifepristone The serum concentration of Fluvastatin can be increased when it is combined with Mifepristone. PimozideMifepristone The serum concentration of Pimozide can be increased when it is combined with Mifepristone. QuinidineMifepristone The serum concentration of Quinidine can be increased when it is combined with Mifepristone. SimvastatinMifepristone The risk or severity of myopathy and rhabdomyolysis can be increased when Mifepristone is combined with Simvastatin.