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

Pharm Res. 2017 Aug;34(8):1570-1583. doi: 10.1007/s11095-017-2168-5. Epub 2017 May 8.


Purpose: To demonstrate the relative importance of organic anion-transporting polypeptides (OATPs) and cytochrome P450 3A (CYP3A) in the hepatic elimination of substrate drugs.

Methods: 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 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.

Results: 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.

Conclusions: 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.

Keywords: Extended clearance concept; Hepatic uptake; Metabolism; Rate-determining process.

MeSH terms

  • Adult
  • Cytochrome P-450 CYP3A / metabolism*
  • Cytochrome P-450 CYP3A Inhibitors / pharmacokinetics
  • Drug Interactions
  • Drug Therapy, Combination
  • Humans
  • Liver / metabolism*
  • Male
  • Maximum Tolerated Dose
  • Organic Anion Transporters / metabolism*
  • Young Adult


  • Cytochrome P-450 CYP3A Inhibitors
  • Organic Anion Transporters
  • Cytochrome P-450 CYP3A