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Research ArticleMetabolism, Transport, and Pharmacogenomics

Cynomolgus Monkey as a Potential Model to Assess Drug Interactions Involving Hepatic Organic Anion Transporting Polypeptides: In Vitro, In Vivo, and In Vitro-to-In Vivo Extrapolation

Hong Shen, Zheng Yang, Gabe Mintier, Yong-Hae Han, Cliff Chen, Praveen Balimane, Mohammed Jemal, Weiping Zhao, Renjie Zhang, Sanjith Kallipatti, Sabariya Selvam, Sunil Sukrutharaj, Prasad Krishnamurthy, Punit Marathe and A. David Rodrigues
Journal of Pharmacology and Experimental Therapeutics March 2013, 344 (3) 673-685; DOI: https://doi.org/10.1124/jpet.112.200691
Hong Shen
Departments of Pharmaceutical Candidate Optimization (H.S., Z.Y., Y.-H.H., C.C., P.B., M.J., W.Z., P.M., A.D.R.) and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Molecular Biology, Bristol-Myers Squibb Biocon R&D Center, Bangalore, India (S.K., Sa.S., Su.S., P.K.); and Department of Bioanalytical Service, WuXi AppTec Co., Ltd, Shanghai, China (R.Z.)
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Zheng Yang
Departments of Pharmaceutical Candidate Optimization (H.S., Z.Y., Y.-H.H., C.C., P.B., M.J., W.Z., P.M., A.D.R.) and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Molecular Biology, Bristol-Myers Squibb Biocon R&D Center, Bangalore, India (S.K., Sa.S., Su.S., P.K.); and Department of Bioanalytical Service, WuXi AppTec Co., Ltd, Shanghai, China (R.Z.)
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Gabe Mintier
Departments of Pharmaceutical Candidate Optimization (H.S., Z.Y., Y.-H.H., C.C., P.B., M.J., W.Z., P.M., A.D.R.) and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Molecular Biology, Bristol-Myers Squibb Biocon R&D Center, Bangalore, India (S.K., Sa.S., Su.S., P.K.); and Department of Bioanalytical Service, WuXi AppTec Co., Ltd, Shanghai, China (R.Z.)
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Yong-Hae Han
Departments of Pharmaceutical Candidate Optimization (H.S., Z.Y., Y.-H.H., C.C., P.B., M.J., W.Z., P.M., A.D.R.) and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Molecular Biology, Bristol-Myers Squibb Biocon R&D Center, Bangalore, India (S.K., Sa.S., Su.S., P.K.); and Department of Bioanalytical Service, WuXi AppTec Co., Ltd, Shanghai, China (R.Z.)
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Cliff Chen
Departments of Pharmaceutical Candidate Optimization (H.S., Z.Y., Y.-H.H., C.C., P.B., M.J., W.Z., P.M., A.D.R.) and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Molecular Biology, Bristol-Myers Squibb Biocon R&D Center, Bangalore, India (S.K., Sa.S., Su.S., P.K.); and Department of Bioanalytical Service, WuXi AppTec Co., Ltd, Shanghai, China (R.Z.)
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Praveen Balimane
Departments of Pharmaceutical Candidate Optimization (H.S., Z.Y., Y.-H.H., C.C., P.B., M.J., W.Z., P.M., A.D.R.) and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Molecular Biology, Bristol-Myers Squibb Biocon R&D Center, Bangalore, India (S.K., Sa.S., Su.S., P.K.); and Department of Bioanalytical Service, WuXi AppTec Co., Ltd, Shanghai, China (R.Z.)
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Mohammed Jemal
Departments of Pharmaceutical Candidate Optimization (H.S., Z.Y., Y.-H.H., C.C., P.B., M.J., W.Z., P.M., A.D.R.) and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Molecular Biology, Bristol-Myers Squibb Biocon R&D Center, Bangalore, India (S.K., Sa.S., Su.S., P.K.); and Department of Bioanalytical Service, WuXi AppTec Co., Ltd, Shanghai, China (R.Z.)
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Weiping Zhao
Departments of Pharmaceutical Candidate Optimization (H.S., Z.Y., Y.-H.H., C.C., P.B., M.J., W.Z., P.M., A.D.R.) and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Molecular Biology, Bristol-Myers Squibb Biocon R&D Center, Bangalore, India (S.K., Sa.S., Su.S., P.K.); and Department of Bioanalytical Service, WuXi AppTec Co., Ltd, Shanghai, China (R.Z.)
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Renjie Zhang
Departments of Pharmaceutical Candidate Optimization (H.S., Z.Y., Y.-H.H., C.C., P.B., M.J., W.Z., P.M., A.D.R.) and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Molecular Biology, Bristol-Myers Squibb Biocon R&D Center, Bangalore, India (S.K., Sa.S., Su.S., P.K.); and Department of Bioanalytical Service, WuXi AppTec Co., Ltd, Shanghai, China (R.Z.)
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Sanjith Kallipatti
Departments of Pharmaceutical Candidate Optimization (H.S., Z.Y., Y.-H.H., C.C., P.B., M.J., W.Z., P.M., A.D.R.) and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Molecular Biology, Bristol-Myers Squibb Biocon R&D Center, Bangalore, India (S.K., Sa.S., Su.S., P.K.); and Department of Bioanalytical Service, WuXi AppTec Co., Ltd, Shanghai, China (R.Z.)
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Sabariya Selvam
Departments of Pharmaceutical Candidate Optimization (H.S., Z.Y., Y.-H.H., C.C., P.B., M.J., W.Z., P.M., A.D.R.) and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Molecular Biology, Bristol-Myers Squibb Biocon R&D Center, Bangalore, India (S.K., Sa.S., Su.S., P.K.); and Department of Bioanalytical Service, WuXi AppTec Co., Ltd, Shanghai, China (R.Z.)
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Sunil Sukrutharaj
Departments of Pharmaceutical Candidate Optimization (H.S., Z.Y., Y.-H.H., C.C., P.B., M.J., W.Z., P.M., A.D.R.) and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Molecular Biology, Bristol-Myers Squibb Biocon R&D Center, Bangalore, India (S.K., Sa.S., Su.S., P.K.); and Department of Bioanalytical Service, WuXi AppTec Co., Ltd, Shanghai, China (R.Z.)
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Prasad Krishnamurthy
Departments of Pharmaceutical Candidate Optimization (H.S., Z.Y., Y.-H.H., C.C., P.B., M.J., W.Z., P.M., A.D.R.) and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Molecular Biology, Bristol-Myers Squibb Biocon R&D Center, Bangalore, India (S.K., Sa.S., Su.S., P.K.); and Department of Bioanalytical Service, WuXi AppTec Co., Ltd, Shanghai, China (R.Z.)
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Punit Marathe
Departments of Pharmaceutical Candidate Optimization (H.S., Z.Y., Y.-H.H., C.C., P.B., M.J., W.Z., P.M., A.D.R.) and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Molecular Biology, Bristol-Myers Squibb Biocon R&D Center, Bangalore, India (S.K., Sa.S., Su.S., P.K.); and Department of Bioanalytical Service, WuXi AppTec Co., Ltd, Shanghai, China (R.Z.)
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A. David Rodrigues
Departments of Pharmaceutical Candidate Optimization (H.S., Z.Y., Y.-H.H., C.C., P.B., M.J., W.Z., P.M., A.D.R.) and Genomic Technologies (G.M.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Molecular Biology, Bristol-Myers Squibb Biocon R&D Center, Bangalore, India (S.K., Sa.S., Su.S., P.K.); and Department of Bioanalytical Service, WuXi AppTec Co., Ltd, Shanghai, China (R.Z.)
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Abstract

Organic anion–transporting polypeptides (OATP) 1B1, 1B3, and 2B1 can serve as the loci of drug–drug interactions (DDIs). In the present work, the cynomolgus monkey was evaluated as a potential model for studying OATP-mediated DDIs. Three cynomolgus monkey OATPs (cOATPs), with a high degree of amino acid sequence identity (91.9, 93.5, and 96.6% for OATP1B1, 1B3, and 2B1, respectively) to their human counterparts, were cloned, expressed, and characterized. The cOATPs were stably transfected in human embryonic kidney cells and were functionally similar to the corresponding human OATPs (hOATPs), as evident from the similar uptake rate of typical substrates (estradiol-17β-d-glucuronide, cholecystokinin octapeptide, and estrone-3-sulfate). Moreover, six known hOATP inhibitors exhibited similar IC50 values against cOATPs. To further evaluate the appropriateness of the cynomolgus monkey as a model, a known hOATP substrate [rosuvastatin (RSV)]-inhibitor [rifampicin (RIF)] pair was examined in vitro; the monkey-derived parameters (RSV Km and RIF IC50) were similar (within 3.5-fold) to those obtained with hOATPs and human primary hepatocytes. In vivo, the area under the plasma concentration-time curve of RSV (3 mg/kg, oral) given 1 hour after a single RIF dose (15 mg/kg, oral) was increased 2.9-fold in cynomolgus monkeys, consistent with the value (3.0-fold) reported in humans. A number of in vitro–in vivo extrapolation approaches, considering the fraction of the pathways affected and free versus total inhibitor concentrations, were also explored. It is concluded that the cynomolgus monkey has the potential to serve as a useful model for the assessment of OATP-mediated DDIs in a nonclinical setting.

Footnotes

  • This study is supported by Bristol-Myers Squibb Company.

  • dx.doi.org/10.1124/jpet.112.200691.

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

  • Received September 27, 2012.
  • Accepted January 4, 2013.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 3
1 Mar 2013
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Research ArticleMetabolism, Transport, and Pharmacogenomics

Use of Cynomolgus Monkey to Assess DDIs Involving OATPs

Hong Shen, Zheng Yang, Gabe Mintier, Yong-Hae Han, Cliff Chen, Praveen Balimane, Mohammed Jemal, Weiping Zhao, Renjie Zhang, Sanjith Kallipatti, Sabariya Selvam, Sunil Sukrutharaj, Prasad Krishnamurthy, Punit Marathe and A. David Rodrigues
Journal of Pharmacology and Experimental Therapeutics March 1, 2013, 344 (3) 673-685; DOI: https://doi.org/10.1124/jpet.112.200691

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Research ArticleMetabolism, Transport, and Pharmacogenomics

Use of Cynomolgus Monkey to Assess DDIs Involving OATPs

Hong Shen, Zheng Yang, Gabe Mintier, Yong-Hae Han, Cliff Chen, Praveen Balimane, Mohammed Jemal, Weiping Zhao, Renjie Zhang, Sanjith Kallipatti, Sabariya Selvam, Sunil Sukrutharaj, Prasad Krishnamurthy, Punit Marathe and A. David Rodrigues
Journal of Pharmacology and Experimental Therapeutics March 1, 2013, 344 (3) 673-685; DOI: https://doi.org/10.1124/jpet.112.200691
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