Abstract
Ketoconazole is no longer available for clinical determination of worst-case victim DDI potential for CYP3A-substrate drugs; clarithromycin and itraconazole are the proposed replacements. While ketoconazole DDIs are described by unbound systemic exposures due to absence of carrier-facilitated hepatic uptake, this aspect of clarithromycin and itraconazole disposition has not been investigated. At present, transport of clarithromycin, itraconazole, and hydroxyitraconazole by hepatic OATPs and OCT1 was examined in vitro and in vivo. As for ketoconazole, uptake of clarithromycin, itraconazole, and hydroxyitraconazole into OATP1B1, OATP1B3, OATP2B1, and OCT1 expressing HEK293 cells was not greater than in vector controls. Uptake into these HEK293 cells and human hepatocytes was not impaired by the prototypical OATP, OCT, and NTCP inhibitors, bromosulfophthalein, imipramine, and taurocholate, respectively. In contrast, uptake of the positive controls, atorvastatin for OATPs and metformin for OCT1, was significantly enhanced by relevant transporter expression, and uptake into both these HEK293 cells and human hepatocytes was significantly impaired by prototypical inhibitors. In Oatp1a/1b gene cluster knockout mice, which lack the major hepatic Oatps, and in Oct1/2 knockout mice, ketoconazole, clarithromycin, itraconazole, and hydroxyitraconazole oral exposure was not increased and liver-to-blood partition coefficient (Kp) was not decreased. By contrast relative to wild-type mice, in Oatp1a/1b- and Oct1/2-knockout mice, atorvastatin and metformin oral exposure was significantly increased and liver Kp was significantly decreased. The present studies provide in vitro and in vivo evidence that like ketoconazole, clarithromycin, itraconazole, and hydroxyitraconazole, are not transported into the liver by hepatic uptake transporters, including OATPs and OCT1.
- Transporter-mediated drug/metabolite disposition
- Uptake transporters (OATP, OAT, OCT, PEPT, MCT, NTCP, ASBT, etc.)
- The American Society for Pharmacology and Experimental Therapeutics