Clinical CYP3A Inhibitor Alternatives to Ketoconazole, Clarithromycin and Itraconazole, Are Not Transported into the Liver by Hepatic Organic Anion Transporting Polypeptides and Organic Cation Transporter 1

Abstract

Ketoconazole is no longer available for clinical determination of worst-case victim drug-drug interaction (DDI) potential for cytochrome P450 3A (CYP3A)-substrate drugs; clarithromycin and itraconazole are the proposed replacements. Ketoconazole DDIs are described by unbound systemic exposures due to absence of carrier-facilitated hepatic uptake, but this aspect of clarithromycin and itraconazole disposition has not been investigated. At present, transport of clarithromycin, itraconazole, and hydroxyitraconazole by hepatic organic anion transporting polypeptides (OATPs) and organic cation transporter 1 (OCT1) was examined in vitro and in vivo. As for ketoconazole, uptake of clarithromycin, itraconazole, and hydroxyitraconazole into OATP1B1, OATP1B3, OATP2B1, and OCT1 expressing human embryonic kidney 293 (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 sodium/taurocholate cotransporting polypeptide 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 the liver-to-blood partition coefficient (K p ) 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 K p 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.

Hepatobiliary Disposition of Atovaquone: A Case of Mechanistically Unusual Biliary Clearance

“…Finally, Oatp1a/1b and Oct1/2 knockout mice were used to confirm in vivo relevance of the negative findings from the uptake studies in transporter overexpressing HEK293 cells and human hepatocytes. Although a positive control substrate was not included in the animal studies, large decreases in liver Kp and increases in systemic exposure of statins and metformin have been previously reported in Oatp1a/1b-and Oct1/2-knockout mice, respectively (Higgins et al, 2014). However, liver Kp of atovaquone was comparable in Oatp1a/1b knockout, Oct1/2 knockout and wild-type mice.…”

Physiologically Based Pharmacokinetic Model of Itraconazole and Two of Its Metabolites to Improve the Predictions and the Mechanistic Understanding of CYP3A4 Drug-Drug Interactions

“…However, in vitro data for ND-ITZ were generated during this study to enable future model development. There are conflicting data on hepatic uptake for itraconazole (Yamano et al, 1999;Higgins et al, 2014). In the current model hepatic uptake was set to 1 following the most recent publication, which showed lack of hepatic uptake in in vitro human primary hepatocytes and knockout mice.…”

PBPK Models for CYP3A4 and P‐gp DDI Prediction: A Modeling Network of Rifampicin, Itraconazole, Clarithromycin, Midazolam, Alfentanil, and Digoxin

“…Therefore, the clarithromycin model was adapted to the CYP3A4 expression profile reported by Nishimura et al 20 used in the other models (see Table S7 in Appendix S1). Furthermore, transport by OATP1B3 was removed, according to literature, 21 and the values for pKa, lipophilicity, fraction unbound, and CYP3A4 K M were fixed to literature values. The adapted model precisely captures the plasma concentration-time profiles of all investigated studies with very low GMFEs (1.16 for AUC values and 1.11 for C max values; n = 15).…”