TY - JOUR T1 - Organic anion transporting polypeptide (OATP) genes are not induced by the pregnane X receptor (PXR) activator rifampin: studies in hepatocytes in vitro and in monkeys in vivo JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.119.088922 SP - dmd.119.088922 AU - Congrong Niu AU - Yujin Wang AU - Xiaofeng Zhao AU - Sam Tep AU - Eisuke Murakami AU - Raju Subramanian AU - Bill Smith AU - Yurong Lai Y1 - 2019/01/01 UR - http://dmd.aspetjournals.org/content/early/2019/10/03/dmd.119.088922.abstract N2 - Induction potentials of the pregnane X receptor (PXR) activator rifampin (RIF) on transporter genes (e.g OATPs) are still in its infancy or remain controversial in the field. The present investigations characterized changes in transporter gene expression by RIF in sandwich-cultured hepatocytes from multiple donors of human and cynomolgus monkey using qRT-PCR method. Three day treatment of RIF significantly induced CYP3A4 (~60-fold induction), but not CYP1A2 and CYP2D6 genes. SLC51B was the most highly induced uptake transporter gene (>10-fold) in both human and monkey hepatocytes. A greater induction of CYP2C9 was observed in monkey hepatocytes than that in human. ABCB1 and ABCC2 were induced slightly above 2-fold in human and monkey hepatocytes and appeared to be dose-dependent. The induction of OATP and other transporter genes was generally less than 2-fold and considered not clinically relevant. SLCO2B1 was not detectable in monkey hepatocytes. To investigate in vivo OATP induction, RIF (18 mg/kg/day) was orally dosed to cynomolgus monkeys for seven days. Pitavastatin and antipyrine were intravenously dosed before and after RIF treatment as exogenous probes of OATP and CYP activities, respectively. Plasma coproporphyrin I (CP-I) and III (CP-III) were measured as OATP endogenous biomarkers. While a significant increase of antipyrine clearance was observed after RIF treatment, the plasma exposures of pitavastatin, CP-I and CP-III remained unchanged, suggesting that OATP function was not significantly altered. The results suggested that OATP transporters were not significantly induced by PXR ligand RIF. The data are consistent with current regulatory guidances that the in vitro characterization of transporter induction during drug development is not required.SIGNIFICANCE STATEMENT In the present studies, the comparison of RIF treatment on changes in expression of transporter genes was done in vitro, for the first time, between human and monkey. Rifampin induction of OATP genes was not detected in sandwich-cultured human and monkey hepatocytes. OATP functions measured by OATP probe pitavastatin and endogenous marker coproporphyrins were not altered in monkeys in vivo by seven day rifampin treatment. The data suggested that OATP transporters are unlikely induced by the PXR ligand rifampin, which are consistent with current regulatory guidances that the in vitro characterization of OATP1B induction during drug development is not required. ER -