Abstract

Farnesoid X receptor (FXR) is a nuclear receptor known to markedly alter expression of major transporters and enzymes in liver. However, its effects toward OATP1B1 and OATP1B3 remain poorly characterized. Therefore, the present study was aimed at determining the effects of chenodeoxycholic acid (CDCA), a naturally occurring FXR agonist, on OATP1B expression in cynomolgus monkeys. Multiple administration of 50 and 100 mg/kg CDCA was first shown to significantly repress mRNA expression of SLCO1B1/3 approximately 60% to 80% in monkey livers. It also suppressed cytochrome P450 (CYP)7A1-mRNA and induced OSTα/β-mRNA, which are well known targets of FXR and determinants of bile acid homeostasis. CDCA concomitantly decreased OATP1B protein abundance by approximately 60% in monkey liver. In contrast, multiple doses of 15 mg/kg rifampin (RIF), a pregnane X receptor (PXR) agonist, had no effect on hepatic OATP1B protein although it induced the intestinal P-gp and MR2 proteins by ~2-fold. Moreover, multiple doses of CDCA resulted in a steady ~2- to 10-fold increase of the OATP1B biomarkers coproporphyrins (CPs) in the plasma samples collected prior to each CDCA dose. Additionally, 3.4- to 11.2-fold increases of CPI and CPIII AUCs were observed after multiple administrations compared to the single dose and vehicle administration dosing groups. Taken together, these data suggest that CDCA represses the expression of OATP1B1 and OATP1B3 in monkeys. Further investigation of OATP1B down-regulation by FXR in humans is warranted, as such down-regulation effects may be involved in bile acid hemostasis and potential drug interactions in man.

Significance Statement Using gene expression and proteomics tools, as well as endogenous biomarker data, for the first time, we have demonstrated that OATP1B expression was suppressed and its activity was reduced in the cynomolgus monkeys following oral administration of 50 and 100 mg/kg/day CDCA, a FXR agonist, for 8 days. These results lead to a better understanding of OATP1B down-regulation by CDCA and its role on bile acid and drug disposition.