title: 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.
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 IC(50) 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 K(m) and RIF IC(50)) 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.
authors.affiliation: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA. hong.shen1@bms.com
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Gabe
authors.initials: G
authors.lastname: Mintier
authors.forename: Yong-Hae
authors.initials: YH
authors.lastname: Han
authors.forename: Cliff
authors.initials: C
authors.lastname: Chen
authors.forename: Praveen
authors.initials: P
authors.lastname: Balimane
authors.forename: Mohammed
authors.initials: M
authors.lastname: Jemal
authors.forename: Weiping
authors.initials: W
authors.lastname: Zhao
authors.forename: Renjie
authors.initials: R
authors.lastname: Zhang
authors.forename: Sanjith
authors.initials: S
authors.lastname: Kallipatti
authors.forename: Sabariya
authors.initials: S
authors.lastname: Selvam
authors.forename: Sunil
authors.initials: S
authors.lastname: Sukrutharaj
authors.forename: Prasad
authors.initials: P
authors.lastname: Krishnamurthy
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.forename: A David
authors.initials: AD
authors.lastname: Rodrigues
mesh_terms: D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D003001:Cloning, Molecular / Q000379:methods; D004347:Drug Interactions; D005464:Fluorobenzenes / Q000494:pharmacology; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008252:Macaca fascicularis / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D012293:Rifampin / Q000494:pharmacology; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D005464:Fluorobenzenes; D027361:Organic Anion Transporters; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D012293:Rifampin