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

作者：Yoshikado Takashi; Maeda Kazuya; Furihata Sawako; Terashima Hanano; Nakayama Takeshi; Ishigame Keiko; Tsunemoto Kazunobu; Kusuhara Hiroyuki; Furihata Ken ichi; Sugiyama Yuichi^*

来源：Pharmaceutical Research, 2017, 34(8): 1570-1583.

DOI：10.1007/s11095-017-2168-5

• Extended clearance concept
• Hepatic uptake
• Metabolism
• Rate-determining process

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; 600 mg, p.o.) and itraconazole (CYP3A inhibitor; 200 mg, i.v.) were coadministered with the cocktail in the second and third phases, respectively. Based on the extended clearance concept, in vivo beta values (fraction of metabolism plus biliary excretion among all the intracellular fates of drugs including basolateral efflux) and R-dif values (ratio of diffusional uptake to active uptake) were estimated.
Rifampicin increased plasma AUCs of bosentan (x3.2), repaglinide (x1.9), clarithromycin (x1.9) and simeprevir (x7.2). Itraconazole increased those of clarithromycin (x2.3), simeprevir (x2.2) and midazolam (x3.7), which had relatively small beta values. The plasma AUC of bosentan (with relatively large beta and small R-dif) was dominated by OATP-mediated uptake. The AUC of simeprevir was also dominated by OATP-mediated uptake because of its small R-dif 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.

• 出版日期2017-8
• 单位RIKEN