CYP1A2 down-regulation by obeticholic acid: usefulness as a positive control for the in vitro evaluation of drug-drug interactions

Abstract CYP down-regulation is a mechanism of drug-drug interaction encountered in pharmaceutical development which is difficult to evaluate in vitro because of the scarcity of evidence. A clinical study of obeticholic acid (OCA) with caffeine [Edwards et al. Adv Ther. 2017;34:2120] suggested that OCA may be a useful positive control to establish a method to evaluate CYP1A2 down-regulation and to investigate the mechanism of its down-regulation. In the present study, we investigated the ability of OCA to down-regulate CYP1A2 in human hepatocytes. OCA suppressed CYP1A2 mRNA expression and CYP1A2 enzyme activity without causing direct inhibition of CYP1A2 or cytotoxicity, suggesting that OCA down-regulates CYP1A2 in vitro. OCA significantly suppressed the induction of CYP1A2 mRNA expression by omeprazole in a concentration-dependent manner, suggesting that a combination of inducers and new chemical entities (NCEs) would be helpful to investigate the mechanism of CYP1A2 down-regulation and to evaluate the potential of NCEs for down-regulation and investigate their down-regulation mechanism. We also showed that CYP1A2 was transcriptionally down-regulated by OCA and that a reduction in aryl hydrocarbon receptor mRNA expression is a possible mechanism of CYP1A2 down-regulation by OCA. These results indicate that OCA would be a suitable positive control for studies of CYP1A2 down-regulation.