Inhibitory effects of ketoconazole and rifampin on OAT1 and OATP1B1 transport activities: considerations on drug-drug interactions.
Summary of "Inhibitory effects of ketoconazole and rifampin on OAT1 and OATP1B1 transport activities: considerations on drug-drug interactions."
Ketoconazole and rifampin are the most widely used compounds examined in recent drug-drug interaction (DDI) studies, and they have multiple roles in modulating drug metabolizing enzymes and transporters. To determine the underlying mechanisms of DDI, this study was performed to investigate the inhibitory effects of ketoconazole and rifampin on the functions of OAT1 and OATP1B1, and to evaluate the potential of ketoconazole and rifampin for DDI with substrate drugs for these transporters in a clinical setting. Ketoconazole inhibited OATP1B1-mediated transport activity, while rifampin inhibited OAT1 and OATP1B1. Inhibition by rifampin and ketoconazole of the uptake of olmesartan, a substrate for OAT1 and OATP1B1, was evaluated in oocytes overexpressing these transporters. The K(i) values for rifampin on OAT1 and OATP1B1-mediated olmesartan uptake were 62.2 and 4.42 µM, respectively, and the K(i) value for ketoconazole on OATP1B1-mediated olmesartan uptake was 66.1 µM. As measured plasma concentrations of rifampin and ketoconazole were 7.29 and 6.4-13.3 µM, respectively, the likelihood of an OATP1B1-mediated drug-drug interaction between rifampin and olmesartan is thought to be possible, whereas OAT1 or OATP1B1-mediated DDI between rifampin or ketoconazole and olmesartan appears unlikely in the clinical setting. Copyright © 2011 John Wiley & Sons, Ltd.
Department of Pharmaceutics, College of Pharmacy, Dankook University, Cheonan 330-714, Korea.
This article was published in the following journal.
Name: Biopharmaceutics & drug disposition
Medical and Biotech [MESH] Definitions
A semisynthetic antibiotic produced from Streptomyces mediterranei. It has a broad antibacterial spectrum, including activity against several forms of Mycobacterium. In susceptible organisms it inhibits DNA-dependent RNA polymerase activity by forming a stable complex with the enzyme. It thus suppresses the initiation of RNA synthesis. Rifampin is bactericidal, and acts on both intracellular and extracellular organisms. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, p1160)
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