title: Evaluation of cynomolgus monkeys for the identification of endogenous biomarkers for hepatic transporter inhibition and as a translatable model to predict pharmacokinetic interactions with statins in humans.
abstract: Inhibition of hepatic transporters such as organic anion transporting polypeptides (OATPs) 1B can cause drug-drug interactions (DDIs). Determining the impact of perpetrator drugs on the plasma exposure of endogenous substrates for OATP1B could be valuable to assess the risk for DDIs early in drug development. As OATP1B orthologs are well conserved between human and monkey, we assessed in cynomolgus monkeys the endogenous OATP1B substrates that are potentially suitable to assess DDI risk in humans. The effect of rifampin (RIF), a potent inhibitor for OATP1B, on plasma exposure of endogenous substrates of hepatic transporters was measured. From the 18 biomarkers tested, RIF (18 mg/kg, oral) caused significant elevation of plasma unconjugated and conjugated bilirubin, which may be attributed to inhibition of cOATP1B1 and cOATP1B3 based on in vitro to in vivo extrapolation analysis. To further evaluate whether cynomolgus monkeys are a suitable translational model to study OATP1B-mediated DDIs, we determined the inhibitory effect of RIF on in vitro transport and pharmacokinetics of rosuvastatin (RSV) and atorvastatin (ATV). RIF strongly inhibited the uptake of RSV and ATV by cOATP1B1 and cOATP1B3 in vitro. In agreement with clinical observations, RIF (18 mg/kg, oral) significantly decreased plasma clearance and increased the area under the plasma concentration curve (AUC) of intravenously administered RSV by 2.8- and 2.7-fold, and increased the AUC and maximum plasma concentration of orally administered RSV by 6- and 10.3-fold, respectively. In contrast to clinical findings, RIF did not significantly increase plasma exposure of either intravenous or orally administered ATV, indicating species differences in the rate-limiting elimination pathways.
authors: Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C., G.H.C., K.O., S.W., X.C., D.N., J.C.P., G.S., J.P., A.L., M.J.S., R.E.); Translational Medicine Research Centre, Singapore (S.J.S., R.S., H.H., A.F., C.K.N.) xiaoyan_chu@merck.com.
authors: Xiaoyan
authors: X
authors: Chu
authors: Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C., G.H.C., K.O., S.W., X.C., D.N., J.C.P., G.S., J.P., A.L., M.J.S., R.E.); Translational Medicine Research Centre, Singapore (S.J.S., R.S., H.H., A.F., C.K.N.).
authors: Shian-Jiun
authors: SJ
authors: Shih
authors: Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C., G.H.C., K.O., S.W., X.C., D.N., J.C.P., G.S., J.P., A.L., M.J.S., R.E.); Translational Medicine Research Centre, Singapore (S.J.S., R.S., H.H., A.F., C.K.N.).
authors: Rachel
authors: R
authors: Shaw
authors: Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C., G.H.C., K.O., S.W., X.C., D.N., J.C.P., G.S., J.P., A.L., M.J.S., R.E.); Translational Medicine Research Centre, Singapore (S.J.S., R.S., H.H., A.F., C.K.N.).
authors: Hannes
authors: H
authors: Hentze
authors: Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C., G.H.C., K.O., S.W., X.C., D.N., J.C.P., G.S., J.P., A.L., M.J.S., R.E.); Translational Medicine Research Centre, Singapore (S.J.S., R.S., H.H., A.F., C.K.N.).
authors: Grace H
authors: GH
authors: Chan
authors: Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C., G.H.C., K.O., S.W., X.C., D.N., J.C.P., G.S., J.P., A.L., M.J.S., R.E.); Translational Medicine Research Centre, Singapore (S.J.S., R.S., H.H., A.F., C.K.N.).
authors: Karen
authors: K
authors: Owens
authors: Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C., G.H.C., K.O., S.W., X.C., D.N., J.C.P., G.S., J.P., A.L., M.J.S., R.E.); Translational Medicine Research Centre, Singapore (S.J.S., R.S., H.H., A.F., C.K.N.).
authors: Shubing
authors: S
authors: Wang
authors: Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C., G.H.C., K.O., S.W., X.C., D.N., J.C.P., G.S., J.P., A.L., M.J.S., R.E.); Translational Medicine Research Centre, Singapore (S.J.S., R.S., H.H., A.F., C.K.N.).
authors: Xiaoxin
authors: X
authors: Cai
authors: Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C., G.H.C., K.O., S.W., X.C., D.N., J.C.P., G.S., J.P., A.L., M.J.S., R.E.); Translational Medicine Research Centre, Singapore (S.J.S., R.S., H.H., A.F., C.K.N.).
authors: Deborah
authors: D
authors: Newton
authors: Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C., G.H.C., K.O., S.W., X.C., D.N., J.C.P., G.S., J.P., A.L., M.J.S., R.E.); Translational Medicine Research Centre, Singapore (S.J.S., R.S., H.H., A.F., C.K.N.).
authors: Jose
authors: J
authors: Castro-Perez
authors: Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C., G.H.C., K.O., S.W., X.C., D.N., J.C.P., G.S., J.P., A.L., M.J.S., R.E.); Translational Medicine Research Centre, Singapore (S.J.S., R.S., H.H., A.F., C.K.N.).
authors: Gino
authors: G
authors: Salituro
authors: Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C., G.H.C., K.O., S.W., X.C., D.N., J.C.P., G.S., J.P., A.L., M.J.S., R.E.); Translational Medicine Research Centre, Singapore (S.J.S., R.S., H.H., A.F., C.K.N.).
authors: Jairam
authors: J
authors: Palamanda
authors: Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C., G.H.C., K.O., S.W., X.C., D.N., J.C.P., G.S., J.P., A.L., M.J.S., R.E.); Translational Medicine Research Centre, Singapore (S.J.S., R.S., H.H., A.F., C.K.N.).
authors: Aaron
authors: A
authors: Fernandis
authors: Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C., G.H.C., K.O., S.W., X.C., D.N., J.C.P., G.S., J.P., A.L., M.J.S., R.E.); Translational Medicine Research Centre, Singapore (S.J.S., R.S., H.H., A.F., C.K.N.).
authors: Choon Keow
authors: CK
authors: Ng
authors: Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C., G.H.C., K.O., S.W., X.C., D.N., J.C.P., G.S., J.P., A.L., M.J.S., R.E.); Translational Medicine Research Centre, Singapore (S.J.S., R.S., H.H., A.F., C.K.N.).
authors: Andy
authors: A
authors: Liaw
authors: Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C., G.H.C., K.O., S.W., X.C., D.N., J.C.P., G.S., J.P., A.L., M.J.S., R.E.); Translational Medicine Research Centre, Singapore (S.J.S., R.S., H.H., A.F., C.K.N.).
authors: Mary J
authors: MJ
authors: Savage
authors: Merck Sharp & Dohme Corporation, Kenilworth, New Jersey (X.C., G.H.C., K.O., S.W., X.C., D.N., J.C.P., G.S., J.P., A.L., M.J.S., R.E.); Translational Medicine Research Centre, Singapore (S.J.S., R.S., H.H., A.F., C.K.N.).
authors: Raymond
authors: R
authors: Evers
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001663:Bilirubin / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D065693:Cytochrome P-450 Enzyme Inducers / Q000008:administration & dosage / Q000009:adverse effects*; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D057809:HEK293 Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D049990:Membrane Transport Modulators / Q000008:administration & dosage / Q000009:adverse effects*; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013045:Species Specificity
chemical_list: D015415:Biomarkers; D065693:Cytochrome P-450 Enzyme Inducers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D049990:Membrane Transport Modulators; D027361:Organic Anion Transporters; D020033:Protein Isoforms; D011994:Recombinant Proteins; C016266:bilirubin glucuronate; D001663:Bilirubin