A Clinical Cassette Dosing Study for Evaluating the Contribution of Hepatic OATPs and CYP3A to Drug-Drug Interactions.

Abstract

To demonstrate the relative importance of organic anion-transporting polypeptides (OATPs) and cytochrome P450 3A (CYP3A) in the hepatic elimination of substrate drugs. A cocktail of subtherapeutic doses of bosentan, repaglinide, clarithromycin, darunavir, simeprevir, and midazolam (CYP3A probe) was administered orally to eight healthy volunteers. Rifampicin (OATP inhibitor; 600mg, p.o.) and itraconazole (CYP3A inhibitor; 200mg, i.v.) were coadministered with the cocktail in the second and third phases, respectively. Based on the extended clearance concept, in vivo β values (fraction of metabolism plus biliary excretion among all the intracellular fates of drugs including basolateral efflux) and Rdif values (ratio of diffusional uptake to active uptake) were estimated. Rifampicin increased plasma AUCs of bosentan (×3.2), repaglinide (×1.9), clarithromycin (×1.9) and simeprevir (×7.2). Itraconazole increased those of clarithromycin (×2.3), simeprevir (×2.2) and midazolam (×3.7), which had relatively small β values. The plasma AUC of bosentan (with relatively large β and small Rdif) was dominated by OATP-mediated uptake. The AUC of simeprevir was also dominated by OATP-mediated uptake because of its small Rdif value. The DDI study clarified the rate-determining processes of OATP/CYP3A substrates. Our analyses provide valuable information for predicting complex drug-drug interactions involving multiple processes.