title: Cynomolgus Monkey as a Clinically Relevant Model to Study Transport Involving Renal Organic Cation Transporters: In Vitro and In Vivo Evaluation.
abstract: Organic cation transporter (OCT) 2, multidrug and toxin extrusion protein (MATE) 1, and MATE2K mediate the renal secretion of various cationic drugs and can serve as the loci of drug-drug interactions (DDI). To support the evaluation of cynomolgus monkey as a surrogate model for studying human organic cation transporters, monkey genes were cloned and shown to have a high degree of amino acid sequence identity versus their human counterparts (93.7, 94.7, and 95.4% for OCT2, MATE1, and MATE2K, respectively). Subsequently, the three transporters were individually stably expressed in human embryonic kidney (HEK) 293 cells and their properties (substrate selectivity, time course, pH dependence, and kinetics) were found to be comparable to the corresponding human form. For example, six known human cation transporter inhibitors, including pyrimethamine (PYR), showed generally similar IC50 values against the monkey transporters (within sixfold). Consistent with the in vitro inhibition of metformin (MFM) transport by PYR (IC50 for cynomolgus OCT2, MATE1, and MATE2K; 1.2 ± 0.38, 0.17 ± 0.04, and 0.25 ± 0.04 µM, respectively), intravenous pretreatment of monkeys with PYR (0.5 mg/kg) decreased the clearance (54 ± 9%) and increased in the area under the plasma concentration-time curve of MFM (AUC ratio versus control = 2.23; 90% confidence interval of 1.57 to 3.17). These findings suggest that the cynomolgus monkey may have some utility in support of in vitro-in vivo extrapolations (IVIVEs) involving the inhibition of renal OCT2 and MATEs. In turn, cynomolgus monkey-enabled IVIVEs may inform human DDI risk assessment.
authors.affiliation: Department of Metabolism and Pharmacokinetics (H.S., T.L., X.Q., C.C., R.M.F., A.D.R., P.M., Y.L.) and Department of Bioanalytical Sciences (H.J., C.T., K.T., H.K., J.Z.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Genomic Technologies (K.K.) and Department of Genome Biology (G.M.), Bristol-Myers Squibb Research and Development, Pennington, New Jersey; and Department of Molecular Biology (S.S., P.K.), Bristol-Myers Squibb Biocon R&D Center, Bangalore, India hong.shen1@bms.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Metabolism and Pharmacokinetics (H.S., T.L., X.Q., C.C., R.M.F., A.D.R., P.M., Y.L.) and Department of Bioanalytical Sciences (H.J., C.T., K.T., H.K., J.Z.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Genomic Technologies (K.K.) and Department of Genome Biology (G.M.), Bristol-Myers Squibb Research and Development, Pennington, New Jersey; and Department of Molecular Biology (S.S., P.K.), Bristol-Myers Squibb Biocon R&D Center, Bangalore, India.
authors.forename: Tongtong
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Metabolism and Pharmacokinetics (H.S., T.L., X.Q., C.C., R.M.F., A.D.R., P.M., Y.L.) and Department of Bioanalytical Sciences (H.J., C.T., K.T., H.K., J.Z.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Genomic Technologies (K.K.) and Department of Genome Biology (G.M.), Bristol-Myers Squibb Research and Development, Pennington, New Jersey; and Department of Molecular Biology (S.S., P.K.), Bristol-Myers Squibb Biocon R&D Center, Bangalore, India.
authors.forename: Hao
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Metabolism and Pharmacokinetics (H.S., T.L., X.Q., C.C., R.M.F., A.D.R., P.M., Y.L.) and Department of Bioanalytical Sciences (H.J., C.T., K.T., H.K., J.Z.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Genomic Technologies (K.K.) and Department of Genome Biology (G.M.), Bristol-Myers Squibb Research and Development, Pennington, New Jersey; and Department of Molecular Biology (S.S., P.K.), Bristol-Myers Squibb Biocon R&D Center, Bangalore, India.
authors.forename: Craig
authors.initials: C
authors.lastname: Titsch
authors.affiliation: Department of Metabolism and Pharmacokinetics (H.S., T.L., X.Q., C.C., R.M.F., A.D.R., P.M., Y.L.) and Department of Bioanalytical Sciences (H.J., C.T., K.T., H.K., J.Z.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Genomic Technologies (K.K.) and Department of Genome Biology (G.M.), Bristol-Myers Squibb Research and Development, Pennington, New Jersey; and Department of Molecular Biology (S.S., P.K.), Bristol-Myers Squibb Biocon R&D Center, Bangalore, India.
authors.forename: Kristin
authors.initials: K
authors.lastname: Taylor
authors.affiliation: Department of Metabolism and Pharmacokinetics (H.S., T.L., X.Q., C.C., R.M.F., A.D.R., P.M., Y.L.) and Department of Bioanalytical Sciences (H.J., C.T., K.T., H.K., J.Z.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Genomic Technologies (K.K.) and Department of Genome Biology (G.M.), Bristol-Myers Squibb Research and Development, Pennington, New Jersey; and Department of Molecular Biology (S.S., P.K.), Bristol-Myers Squibb Biocon R&D Center, Bangalore, India.
authors.forename: Hamza
authors.initials: H
authors.lastname: Kandoussi
authors.affiliation: Department of Metabolism and Pharmacokinetics (H.S., T.L., X.Q., C.C., R.M.F., A.D.R., P.M., Y.L.) and Department of Bioanalytical Sciences (H.J., C.T., K.T., H.K., J.Z.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Genomic Technologies (K.K.) and Department of Genome Biology (G.M.), Bristol-Myers Squibb Research and Development, Pennington, New Jersey; and Department of Molecular Biology (S.S., P.K.), Bristol-Myers Squibb Biocon R&D Center, Bangalore, India.
authors.forename: Xi
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Department of Metabolism and Pharmacokinetics (H.S., T.L., X.Q., C.C., R.M.F., A.D.R., P.M., Y.L.) and Department of Bioanalytical Sciences (H.J., C.T., K.T., H.K., J.Z.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Genomic Technologies (K.K.) and Department of Genome Biology (G.M.), Bristol-Myers Squibb Research and Development, Pennington, New Jersey; and Department of Molecular Biology (S.S., P.K.), Bristol-Myers Squibb Biocon R&D Center, Bangalore, India.
authors.forename: Cliff
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Metabolism and Pharmacokinetics (H.S., T.L., X.Q., C.C., R.M.F., A.D.R., P.M., Y.L.) and Department of Bioanalytical Sciences (H.J., C.T., K.T., H.K., J.Z.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Genomic Technologies (K.K.) and Department of Genome Biology (G.M.), Bristol-Myers Squibb Research and Development, Pennington, New Jersey; and Department of Molecular Biology (S.S., P.K.), Bristol-Myers Squibb Biocon R&D Center, Bangalore, India.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sukrutharaj
authors.affiliation: Department of Metabolism and Pharmacokinetics (H.S., T.L., X.Q., C.C., R.M.F., A.D.R., P.M., Y.L.) and Department of Bioanalytical Sciences (H.J., C.T., K.T., H.K., J.Z.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Genomic Technologies (K.K.) and Department of Genome Biology (G.M.), Bristol-Myers Squibb Research and Development, Pennington, New Jersey; and Department of Molecular Biology (S.S., P.K.), Bristol-Myers Squibb Biocon R&D Center, Bangalore, India.
authors.forename: Kathy
authors.initials: K
authors.lastname: Kuit
authors.affiliation: Department of Metabolism and Pharmacokinetics (H.S., T.L., X.Q., C.C., R.M.F., A.D.R., P.M., Y.L.) and Department of Bioanalytical Sciences (H.J., C.T., K.T., H.K., J.Z.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Genomic Technologies (K.K.) and Department of Genome Biology (G.M.), Bristol-Myers Squibb Research and Development, Pennington, New Jersey; and Department of Molecular Biology (S.S., P.K.), Bristol-Myers Squibb Biocon R&D Center, Bangalore, India.
authors.forename: Gabe
authors.initials: G
authors.lastname: Mintier
authors.affiliation: Department of Metabolism and Pharmacokinetics (H.S., T.L., X.Q., C.C., R.M.F., A.D.R., P.M., Y.L.) and Department of Bioanalytical Sciences (H.J., C.T., K.T., H.K., J.Z.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Genomic Technologies (K.K.) and Department of Genome Biology (G.M.), Bristol-Myers Squibb Research and Development, Pennington, New Jersey; and Department of Molecular Biology (S.S., P.K.), Bristol-Myers Squibb Biocon R&D Center, Bangalore, India.
authors.forename: Prasad
authors.initials: P
authors.lastname: Krishnamurthy
authors.affiliation: Department of Metabolism and Pharmacokinetics (H.S., T.L., X.Q., C.C., R.M.F., A.D.R., P.M., Y.L.) and Department of Bioanalytical Sciences (H.J., C.T., K.T., H.K., J.Z.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Genomic Technologies (K.K.) and Department of Genome Biology (G.M.), Bristol-Myers Squibb Research and Development, Pennington, New Jersey; and Department of Molecular Biology (S.S., P.K.), Bristol-Myers Squibb Biocon R&D Center, Bangalore, India.
authors.forename: R Marcus
authors.initials: RM
authors.lastname: Fancher
authors.affiliation: Department of Metabolism and Pharmacokinetics (H.S., T.L., X.Q., C.C., R.M.F., A.D.R., P.M., Y.L.) and Department of Bioanalytical Sciences (H.J., C.T., K.T., H.K., J.Z.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Genomic Technologies (K.K.) and Department of Genome Biology (G.M.), Bristol-Myers Squibb Research and Development, Pennington, New Jersey; and Department of Molecular Biology (S.S., P.K.), Bristol-Myers Squibb Biocon R&D Center, Bangalore, India.
authors.forename: Jianing
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Department of Metabolism and Pharmacokinetics (H.S., T.L., X.Q., C.C., R.M.F., A.D.R., P.M., Y.L.) and Department of Bioanalytical Sciences (H.J., C.T., K.T., H.K., J.Z.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Genomic Technologies (K.K.) and Department of Genome Biology (G.M.), Bristol-Myers Squibb Research and Development, Pennington, New Jersey; and Department of Molecular Biology (S.S., P.K.), Bristol-Myers Squibb Biocon R&D Center, Bangalore, India.
authors.forename: A David
authors.initials: AD
authors.lastname: Rodrigues
authors.affiliation: Department of Metabolism and Pharmacokinetics (H.S., T.L., X.Q., C.C., R.M.F., A.D.R., P.M., Y.L.) and Department of Bioanalytical Sciences (H.J., C.T., K.T., H.K., J.Z.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Genomic Technologies (K.K.) and Department of Genome Biology (G.M.), Bristol-Myers Squibb Research and Development, Pennington, New Jersey; and Department of Molecular Biology (S.S., P.K.), Bristol-Myers Squibb Biocon R&D Center, Bangalore, India.
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.affiliation: Department of Metabolism and Pharmacokinetics (H.S., T.L., X.Q., C.C., R.M.F., A.D.R., P.M., Y.L.) and Department of Bioanalytical Sciences (H.J., C.T., K.T., H.K., J.Z.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey; Department of Genomic Technologies (K.K.) and Department of Genome Biology (G.M.), Bristol-Myers Squibb Research and Development, Pennington, New Jersey; and Department of Molecular Biology (S.S., P.K.), Bristol-Myers Squibb Biocon R&D Center, Bangalore, India.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Lai
mesh_terms: D000818:Animals; D002412:Cations / Q000378:metabolism*; D002460:Cell Line; D004347:Drug Interactions / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D008252:Macaca fascicularis; D008687:Metformin / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D011739:Pyrimethamine / Q000378:metabolism
chemical_list: D002412:Cations; D027701:Organic Cation Transport Proteins; D008687:Metformin; D011739:Pyrimethamine