title: Transporter Expression in Liver Tissue from Subjects with Alcoholic or Hepatitis C Cirrhosis Quantified by Targeted Quantitative Proteomics.
abstract: Although data are available on the change of expression/activity of drug-metabolizing enzymes in liver cirrhosis patients, corresponding data on transporter protein expression are not available. Therefore, using quantitative targeted proteomics, we compared our previous data on noncirrhotic control livers (n = 36) with the protein expression of major hepatobiliary transporters, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug and toxin extrusion protein 1 (MATE1), multidrug resistance-associated protein (MRP)2, MRP3, MRP4, sodium taurocholate-cotransporting polypeptide (NTCP), organic anion-transporting polypeptides (OATP)1B1, 1B3, 2B1, organic cation transporter 1 (OCT1), and P-glycoprotein (P-gp) in alcoholic (n = 27) and hepatitis C cirrhosis (n = 30) livers. Compared with control livers, the yield of membrane protein from alcoholic and hepatitis C cirrhosis livers was significantly reduced by 56 and 67%, respectively. The impact of liver cirrhosis on transporter protein expression was transporter-dependent. Generally, reduced protein expression (per gram of liver) was found in alcoholic cirrhosis livers versus control livers, with the exception that the expression of MRP3 was increased, whereas no change was observed for MATE1, MRP2, OATP2B1, and P-gp. In contrast, the impact of hepatitis C cirrhosis on protein expression of transporters (per gram of liver) was diverse, showing an increase (MATE1), decrease (BSEP, MRP2, NTCP, OATP1B3, OCT1, and P-gp), or no change (BCRP, MRP3, OATP1B1, and 2B1). The expression of hepatobiliary transporter protein differed in different diseases (alcoholic versus hepatitis C cirrhosis). Finally, incorporation of protein expression of OATP1B1 in alcoholic cirrhosis into the Simcyp physiologically based pharmacokinetics cirrhosis module improved prediction of the disposition of repaglinide in liver cirrhosis patients. These transporter expression data will be useful in the future to predict transporter-mediated drug disposition in liver cirrhosis patients.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., C.C., E.J.K., J.D.U.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Departments of Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Preclinical PK and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Ardea Biosciences, Inc., San Diego, California (C.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L.,W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.); Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas (S.C.K.).
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., C.C., E.J.K., J.D.U.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Departments of Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Preclinical PK and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Ardea Biosciences, Inc., San Diego, California (C.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L.,W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.); Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas (S.C.K.).
authors.forename: Carol
authors.initials: C
authors.lastname: Collins
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., C.C., E.J.K., J.D.U.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Departments of Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Preclinical PK and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Ardea Biosciences, Inc., San Diego, California (C.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L.,W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.); Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas (S.C.K.).
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Kelly
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., C.C., E.J.K., J.D.U.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Departments of Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Preclinical PK and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Ardea Biosciences, Inc., San Diego, California (C.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L.,W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.); Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas (S.C.K.).
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chu
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., C.C., E.J.K., J.D.U.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Departments of Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Preclinical PK and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Ardea Biosciences, Inc., San Diego, California (C.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L.,W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.); Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas (S.C.K.).
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., C.C., E.J.K., J.D.U.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Departments of Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Preclinical PK and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Ardea Biosciences, Inc., San Diego, California (C.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L.,W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.); Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas (S.C.K.).
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., C.C., E.J.K., J.D.U.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Departments of Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Preclinical PK and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Ardea Biosciences, Inc., San Diego, California (C.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L.,W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.); Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas (S.C.K.).
authors.forename: Guangqing
authors.initials: G
authors.lastname: Xiao
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., C.C., E.J.K., J.D.U.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Departments of Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Preclinical PK and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Ardea Biosciences, Inc., San Diego, California (C.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L.,W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.); Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas (S.C.K.).
authors.forename: Caroline
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., C.C., E.J.K., J.D.U.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Departments of Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Preclinical PK and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Ardea Biosciences, Inc., San Diego, California (C.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L.,W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.); Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas (S.C.K.).
authors.forename: Yurong
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., C.C., E.J.K., J.D.U.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Departments of Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Preclinical PK and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Ardea Biosciences, Inc., San Diego, California (C.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L.,W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.); Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas (S.C.K.).
authors.forename: Mingxiang
authors.initials: M
authors.lastname: Liao
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., C.C., E.J.K., J.D.U.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Departments of Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Preclinical PK and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Ardea Biosciences, Inc., San Diego, California (C.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L.,W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.); Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas (S.C.K.).
authors.forename: Anita
authors.initials: A
authors.lastname: Mathias
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., C.C., E.J.K., J.D.U.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Departments of Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Preclinical PK and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Ardea Biosciences, Inc., San Diego, California (C.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L.,W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.); Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas (S.C.K.).
authors.forename: Raymond
authors.initials: R
authors.lastname: Evers
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., C.C., E.J.K., J.D.U.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Departments of Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Preclinical PK and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Ardea Biosciences, Inc., San Diego, California (C.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L.,W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.); Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas (S.C.K.).
authors.forename: William
authors.initials: W
authors.lastname: Humphreys
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., C.C., E.J.K., J.D.U.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Departments of Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Preclinical PK and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Ardea Biosciences, Inc., San Diego, California (C.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L.,W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.); Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas (S.C.K.).
authors.forename: Cornelis E C A
authors.initials: CE
authors.lastname: Hop
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., C.C., E.J.K., J.D.U.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Departments of Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Preclinical PK and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Ardea Biosciences, Inc., San Diego, California (C.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L.,W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.); Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas (S.C.K.).
authors.forename: Sean C
authors.initials: SC
authors.lastname: Kumer
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (L.W., C.C., E.J.K., J.D.U.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C.); Departments of Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M.); Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, California (L.S., C.E.C.A.H.); Preclinical PK and In Vitro ADME, Biogen, Cambridge, Massachusetts (G.X.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Ardea Biosciences, Inc., San Diego, California (C.L.); Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, New Jersey (Y.L.,W.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Kenilworth, New Jersey (R.E.); Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas (S.C.K.) jash@uw.edu.
authors.forename: Jashvant D
authors.initials: JD
authors.lastname: Unadkat
mesh_terms: D000431:Ethanol / Q000378:metabolism*; D005260:Female; D006526:Hepatitis C / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics / Q000379:methods
chemical_list: C000715087:ABCC2 protein, human; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D020543:Proteome; D000431:Ethanol