title: Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species.
abstract: Inhibition of organic anion-transporting polypeptide (OATP)1B function can lead to serious clinical drug-drug interactions, thus a thorough evaluation of the potential for this type of interaction must be completed during drug development. Therefore, sensitive and specific biomarkers for OATP function that could be used in conjunction with clinical studies are currently in demand. In the present study, preclinical evaluations were conducted to characterize the suitability of coproporphyrins (CPs) I and III as markers of hepatic OATP functional activity. Active uptake of CPs I and III was observed in human embryonic kidney (HEK) 293 cells singly expressing human OATP1B1 (hOATP1B1), hOATP1B3, cynomolgus monkey OATP1B1 (cOATP1B1), or cOATP1B3, as well as human and monkey hepatocytes. Cyclosporin A (100 mg/kg, oral) markedly increased the area under the curve (AUC) plasma concentrations of CPs I and III by 2.6- and 5.2-fold, while rifampicin (15 mg/kg, oral) increased the AUCs by 2.7- and 3.6-fold, respectively. As the systemic exposure increased, the excretion of both isomers in urine rose from 1.6- to 4.3-fold in monkeys. In agreement with this finding, the AUC of rosuvastatin (RSV) in cynomolgus monkeys increased when OATP1B inhibitors were coadministered. In Oatp1a/1b gene cluster knockout mice (Oatp1a/1b(-/-)), CPs in plasma and urine were significantly increased compared with wild-type animals (7.1- to 18.4-fold; P < 0.001), which were also in agreement with the changes in plasma RSV exposure (14.6-fold increase). We conclude that CPs I and III in plasma and urine are novel endogenous biomarkers reflecting hepatic OATP function, and the measurements have the potential to be incorporated into the design of early clinical evaluation.
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey hong.shen1@bms.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Jun
authors.initials: J
authors.lastname: Dai
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Tongtong
authors.initials: T
authors.lastname: Liu
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Yaofeng
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Weiqi
authors.initials: W
authors.lastname: Chen
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Chris
authors.initials: C
authors.lastname: Freeden
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Yingru
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: W Griffith
authors.initials: WG
authors.lastname: Humphreys
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Lai
mesh_terms: D000818:Animals; D019540:Area Under Curve; D003306:Coproporphyrins / Q000097:blood*; D016572:Cyclosporine / Q000493:pharmacokinetics; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008252:Macaca fascicularis; D051379:Mice; D018345:Mice, Knockout; D027361:Organic Anion Transporters / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D012293:Rifampin / Q000493:pharmacokinetics; D000068718:Rosuvastatin Calcium / Q000493:pharmacokinetics
chemical_list: D003306:Coproporphyrins; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; C026971:coproporphyrin III; C031467:coproporphyrin I; D016572:Cyclosporine; D000068718:Rosuvastatin Calcium; D012293:Rifampin