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Research ArticleMetabolism, Transport, and Pharmacogenomics

Evaluation of Rosuvastatin as an Organic Anion Transporting Polypeptide (OATP) Probe Substrate: In Vitro Transport and In Vivo Disposition in Cynomolgus Monkeys

Hong Shen, Hong Su, Tongtong Liu, Ming Yao, Gabe Mintier, Lun Li, R. Marcus Fancher, Ramaswamy Iyer, Punit Marathe, Yurong Lai and A. David Rodrigues
Journal of Pharmacology and Experimental Therapeutics May 2015, 353 (2) 380-391; DOI: https://doi.org/10.1124/jpet.114.221804
Hong Shen
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People’s Republic of China (L.L.)
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Hong Su
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People’s Republic of China (L.L.)
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Tongtong Liu
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People’s Republic of China (L.L.)
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Ming Yao
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People’s Republic of China (L.L.)
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Gabe Mintier
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People’s Republic of China (L.L.)
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Lun Li
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People’s Republic of China (L.L.)
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R. Marcus Fancher
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People’s Republic of China (L.L.)
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Ramaswamy Iyer
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People’s Republic of China (L.L.)
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Punit Marathe
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People’s Republic of China (L.L.)
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Yurong Lai
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People’s Republic of China (L.L.)
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A. David Rodrigues
Pharmaceutical Candidate Optimization (H.Sh., H.Su., T.L., M.Y., R.M.F., R.I., P.M., Y.L., A.D.R.), and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; and Department of Bioanalytical Service, WuXi AppTec Co., Ltd., Shanghai, People’s Republic of China (L.L.)
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Abstract

Organic anion transporting polypeptides (OATPs) mediate hepatic drug uptake and serve as the loci of drug–drug interactions (DDIs). Consequently, there is a major need to develop animal models and refine in vitro–in vivo extrapolations. Therefore, the in vivo disposition of a model OATP substrate, [3H]rosuvastatin (RSV), was studied in the cynomolgus monkey and reported for the first time. After monkeys had received a 3-mg/kg oral dose, mass balance was achieved after bile duct cannulation (mean total recovery of radioactivity of 103.6%). Forty-two percent of the RSV dose was recovered in urine and bile, and the elimination pathways were similar to those reported for human subjects; 61.7%, 39.0%, and 2.9% of the dose was recovered in the feces, bile, and urine, respectively. The high levels of unchanged RSV recovered in urine and bile (26% of the dose) and the relatively low levels of metabolites observed indicated that RSV was eliminated largely by excretion. Also, for the first time, the in vitro inhibitory potential of cyclosporin A (CsA) toward cynomolgus monkey OATPs and sodium-taurocholate cotransporting polypeptide was studied in vitro (primary hepatocytes and transporter-transfected cells). It is concluded that one can study the CsA-RSV DDI in the cynomolgus monkey. For example, the in vitro IC50 values were within 2-fold (monkey versus human), and the increase (versus vehicle control) in the RSV AUC0–inf (6.3-fold) and Cmax (10.2-fold) with CsA (100 mg/kg) was similar to that reported for humans. The results further support the use of the cynomolgus monkey as a model to assess interactions involving OATP inhibition.

Footnotes

    • Received December 6, 2014.
    • Accepted February 18, 2015.
  • This study is supported by Bristol-Myers Squibb Company.

  • dx.doi.org/10.1124/jpet.114.221804.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 353 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 353, Issue 2
1 May 2015
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Use of Cynomolgus Monkey to Assess DDIs Involving OATPs

Hong Shen, Hong Su, Tongtong Liu, Ming Yao, Gabe Mintier, Lun Li, R. Marcus Fancher, Ramaswamy Iyer, Punit Marathe, Yurong Lai and A. David Rodrigues
Journal of Pharmacology and Experimental Therapeutics May 1, 2015, 353 (2) 380-391; DOI: https://doi.org/10.1124/jpet.114.221804

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Use of Cynomolgus Monkey to Assess DDIs Involving OATPs

Hong Shen, Hong Su, Tongtong Liu, Ming Yao, Gabe Mintier, Lun Li, R. Marcus Fancher, Ramaswamy Iyer, Punit Marathe, Yurong Lai and A. David Rodrigues
Journal of Pharmacology and Experimental Therapeutics May 1, 2015, 353 (2) 380-391; DOI: https://doi.org/10.1124/jpet.114.221804
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