RT Journal Article SR Electronic T1 Absence of OATP1B Induction by Rifampin in Cynomolgus Monkeys: Determination Using the Endogenous OATP1B Marker Coproporphyrin and Tissue Gene Expression JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP JPET-AR-2020-000139 DO 10.1124/jpet.120.000139 A1 Yueping Zhang A1 Cliff Chen A1 Shen-Jue Chen A1 Xue-Qing Chen A1 David J. Shuster A1 Pawel D. Puszczalo A1 R. Marcus Fancher A1 Zheng Yang A1 Michael Sinz A1 Hong Shen YR 2020 UL http://jpet.aspetjournals.org/content/early/2020/07/27/jpet.120.000139.abstract AB Organic anion-transporting polypeptide (OATP)1B induction is an evolving mechanism of drug disposition and interaction. However, there are contradictory reports describing OATP1B expression in hepatocytes and liver biopsies after administration of an inducer. This study investigated the in vivo effects of the common inducer rifampin (RIF) on the activity and expression of cynomolgus monkey OATP1B1 and OATP1B3 transporters, which are structurally and functionally similar their human OATP1B counterparts. Multiple doses of oral RIF (15 mg/kg) resulted in a steady 3.9-fold increase of CYP3A biomarker, 4β-hydroxycholesterol (4βHC), in the plasma samples collected before each RIF dose during the treatment period (i.e., predose). In contrast, the predose plasma levels of OATP1B biomarkers coproporphyrin (CP) I and CPIII did not change when compared to RIF treatment. The trough concentration, AUC, and half-life of RIF decreased markedly during RIF treatment, suggesting that RIF induced its own clearance. Consequently, RIF treatment increased CPI and CPIII AUCs substantially after a single administration and, to a lesser extent, after multiple administrations, compared to pre-administration AUCs. In addition, OATP1B1 and OATP1B3 mRNA expressions were not modulated by RIF treatment (0.85- to 1.3-fold) whereas CYP3A8 expression was increased 3.7- to 5.0-fold, which correlated well with the predose levels of CP and 4βHC. Rifampin treatment showed 2.0- to 3.3-fold increases in P-gp, BCRP, and MRP2 expression in the small intestine. Collectively, these findings indicate that monkey OATP1B and OATP1B3 are not induced by RIF and further investigation of OATP1B induction by RIF and other nuclear receptor activators in humans is warranted. Significance Statement In this study, combined endogenous biomarker and gene expression data suggested that RIF did not induce OATP1B in cynomolgus monkeys. For the first time, the study determines transporter gene expression in the nonhuman primate liver, gut, and kidney tissues following administration of RIF for 7 days, leading to a better understanding of the induction of OATP1B and other major drug transporters. Finally, it provides evidence to strengthen the claim that CP is a suitable endogenous probes of OATP1B activity.