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Transporter Expression in Liver Tissue from Subjects with Alcoholic or Hepatitis C Cirrhosis Quantified by Targeted Quantitative Proteomics.
Wang, Li; Collins, Carol; Kelly, Edward J; Chu, Xiaoyan; Ray, Adrian S; Salphati, Laurent; Xiao, Guangqing; Lee, Caroline; Lai, Yurong; Liao, Mingxiang; Mathias, Anita; Evers, Raymond; Humphreys, William; Hop, Cornelis E C A; Kumer, Sean C; Unadkat, Jashvant D.
Afiliação
  • Wang L; 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
  • Collins C; 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
  • Kelly EJ; 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
  • Chu X; 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
  • Ray AS; 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
  • Salphati L; 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
  • Xiao G; 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
  • Lee C; 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
  • Lai Y; 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
  • Liao M; 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
  • Mathias A; 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
  • Evers R; 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
  • Humphreys W; 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
  • Hop CE; 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
  • Kumer SC; 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
  • Unadkat JD; 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
Drug Metab Dispos ; 44(11): 1752-1758, 2016 11.
Article em En | MEDLINE | ID: mdl-27543206
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas de Membrana Transportadoras / Hepatite C / Proteoma / Etanol / Fígado / Cirrose Hepática / Proteínas de Membrana Limite: Female / Humans / Male / Middle aged Idioma: En Revista: Drug Metab Dispos Assunto da revista: FARMACOLOGIA Ano de publicação: 2016 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas de Membrana Transportadoras / Hepatite C / Proteoma / Etanol / Fígado / Cirrose Hepática / Proteínas de Membrana Limite: Female / Humans / Male / Middle aged Idioma: En Revista: Drug Metab Dispos Assunto da revista: FARMACOLOGIA Ano de publicação: 2016 Tipo de documento: Article