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Research ArticleMetabolism, Transport, and Pharmacogenetics

Absence of OATP1B (Organic Anion–Transporting Polypeptide) Induction by Rifampin in Cynomolgus Monkeys: Determination Using the Endogenous OATP1B Marker Coproporphyrin and Tissue Gene Expression

Yueping Zhang, Cliff Chen, Shen-Jue Chen, Xue-Qing Chen, David J. Shuster, Pawel D. Puszczalo, R. Marcus Fancher, Zheng Yang, Michael Sinz and Hong Shen
Journal of Pharmacology and Experimental Therapeutics October 2020, 375 (1) 139-151; DOI: https://doi.org/10.1124/jpet.120.000139
Yueping Zhang
Departments of Metabolism and Pharmacokinetics (Y.Z., C.C., R.M.F., Z.Y., M.S., H.S.), Discovery Toxicology (S.-J.C.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., P.D.P.), Bristol Myers Squibb Company, Princeton, New Jersey
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Cliff Chen
Departments of Metabolism and Pharmacokinetics (Y.Z., C.C., R.M.F., Z.Y., M.S., H.S.), Discovery Toxicology (S.-J.C.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., P.D.P.), Bristol Myers Squibb Company, Princeton, New Jersey
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Shen-Jue Chen
Departments of Metabolism and Pharmacokinetics (Y.Z., C.C., R.M.F., Z.Y., M.S., H.S.), Discovery Toxicology (S.-J.C.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., P.D.P.), Bristol Myers Squibb Company, Princeton, New Jersey
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Xue-Qing Chen
Departments of Metabolism and Pharmacokinetics (Y.Z., C.C., R.M.F., Z.Y., M.S., H.S.), Discovery Toxicology (S.-J.C.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., P.D.P.), Bristol Myers Squibb Company, Princeton, New Jersey
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David J. Shuster
Departments of Metabolism and Pharmacokinetics (Y.Z., C.C., R.M.F., Z.Y., M.S., H.S.), Discovery Toxicology (S.-J.C.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., P.D.P.), Bristol Myers Squibb Company, Princeton, New Jersey
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Pawel D. Puszczalo
Departments of Metabolism and Pharmacokinetics (Y.Z., C.C., R.M.F., Z.Y., M.S., H.S.), Discovery Toxicology (S.-J.C.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., P.D.P.), Bristol Myers Squibb Company, Princeton, New Jersey
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R. Marcus Fancher
Departments of Metabolism and Pharmacokinetics (Y.Z., C.C., R.M.F., Z.Y., M.S., H.S.), Discovery Toxicology (S.-J.C.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., P.D.P.), Bristol Myers Squibb Company, Princeton, New Jersey
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Zheng Yang
Departments of Metabolism and Pharmacokinetics (Y.Z., C.C., R.M.F., Z.Y., M.S., H.S.), Discovery Toxicology (S.-J.C.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., P.D.P.), Bristol Myers Squibb Company, Princeton, New Jersey
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Michael Sinz
Departments of Metabolism and Pharmacokinetics (Y.Z., C.C., R.M.F., Z.Y., M.S., H.S.), Discovery Toxicology (S.-J.C.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., P.D.P.), Bristol Myers Squibb Company, Princeton, New Jersey
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Hong Shen
Departments of Metabolism and Pharmacokinetics (Y.Z., C.C., R.M.F., Z.Y., M.S., H.S.), Discovery Toxicology (S.-J.C.), Discovery Pharmaceutics (X.-Q.C.), and Veterinary Sciences (D.J.S., P.D.P.), Bristol Myers Squibb Company, Princeton, New Jersey
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Abstract

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 with RIF treatment. The trough concentration, area under plasma concentration-time curve (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 with preadministration AUCs. In addition, OATP1B1 and OATP1B3 mRNA expressions were not modulated by RIF treatment (0.85–1.3-fold), whereas CYP3A8 expression was increased 3.7–5.0-fold, which correlated well with the predose levels of CP and 4βHC. Rifampin treatment showed 2.0–3.3-fold increases in P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (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 after 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 coproporphyrin is a suitable endogenous probe of OATP1B activity.

Footnotes

    • Received May 29, 2020.
    • Accepted July 14, 2020.
  • This study is supported by Bristol Myers Squibb Company.

  • https://doi.org/10.1124/jpet.120.000139.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 375 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 375, Issue 1
1 Oct 2020
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Research ArticleMetabolism, Transport, and Pharmacogenetics

Lack of OATP1B Induction by Rifampin in Monkeys

Yueping Zhang, Cliff Chen, Shen-Jue Chen, Xue-Qing Chen, David J. Shuster, Pawel D. Puszczalo, R. Marcus Fancher, Zheng Yang, Michael Sinz and Hong Shen
Journal of Pharmacology and Experimental Therapeutics October 1, 2020, 375 (1) 139-151; DOI: https://doi.org/10.1124/jpet.120.000139

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Research ArticleMetabolism, Transport, and Pharmacogenetics

Lack of OATP1B Induction by Rifampin in Monkeys

Yueping Zhang, Cliff Chen, Shen-Jue Chen, Xue-Qing Chen, David J. Shuster, Pawel D. Puszczalo, R. Marcus Fancher, Zheng Yang, Michael Sinz and Hong Shen
Journal of Pharmacology and Experimental Therapeutics October 1, 2020, 375 (1) 139-151; DOI: https://doi.org/10.1124/jpet.120.000139
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