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Ethnic variability in the expression of hepatic drug transporters: absolute quantification by an optimized targeted quantitative proteomic approach.
Peng, Kuan-wei; Bacon, James; Zheng, Ming; Guo, Yingying; Wang, Michael Zhuo.
Afiliación
  • Peng KW; Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas (K.P., M.Z.W.); Eli Lilly & Company, Indianapolis, Indiana (J.B., Y.G.); and School of Medicine, Stanford University, Stanford, California (M.Z.).
  • Bacon J; Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas (K.P., M.Z.W.); Eli Lilly & Company, Indianapolis, Indiana (J.B., Y.G.); and School of Medicine, Stanford University, Stanford, California (M.Z.).
  • Zheng M; Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas (K.P., M.Z.W.); Eli Lilly & Company, Indianapolis, Indiana (J.B., Y.G.); and School of Medicine, Stanford University, Stanford, California (M.Z.).
  • Guo Y; Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas (K.P., M.Z.W.); Eli Lilly & Company, Indianapolis, Indiana (J.B., Y.G.); and School of Medicine, Stanford University, Stanford, California (M.Z.).
  • Wang MZ; Department of Pharmaceutical Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas (K.P., M.Z.W.); Eli Lilly & Company, Indianapolis, Indiana (J.B., Y.G.); and School of Medicine, Stanford University, Stanford, California (M.Z.) michael.wang@ku.edu.
Drug Metab Dispos ; 43(7): 1045-55, 2015 Jul.
Article en En | MEDLINE | ID: mdl-25926430
Hepatic OATPs 1B1, 1B3 and 2B1, as well as P-gp, play important roles in regulating liver uptake and biliary excretion of drugs. The intrinsic ethnic variability in OATP1B1-mediated hepatic uptake of statins has been proposed to underlie the ethnic variability in plasma exposures of statins between Caucasians and Asians. Using a targeted quantitative proteomic approach, we determined hepatic protein concentrations of OATP1B1, OATP1B3, OATP2B1, P-gp, and PMCA4 (a housekeeping protein) in a panel of human livers (n = 141) and compared protein expression across Caucasian, Asian, African-American, and unidentified donors. Using an optimized protocol that included sodium deoxycholate as a membrane protein solubilizer, the hepatic protein expression levels (mean ± S.D.) of these transporters across all livers were determined to be 15.0 ± 6.0, 16.1 ± 8.1, 4.1 ± 1.3, 0.6 ± 0.2, and 2.4 ± 1.0 fmol/µg of total membrane protein, respectively. The scaling factor was 3.5 mg of total membrane protein in 100 mg of wet liver tissue. OATP1B1 protein expression was significantly associated with the c.388A>G (rs2306283, N130D) single nucleotide polymorphism. When compared across ethnicity, the hepatic expression levels of OATP1B1 and OATP1B3 were unexpectedly higher in Asians relative to Caucasians, suggesting that hepatic OATP expression alone does not explain the increased systemic statin levels in Asians compared with Caucasians. These findings may help improve physiologically based pharmacokinetic modeling to predict statin pharmacokinetic profiles and enable extrapolation of pharmacokinetic data of OATP substrates across ethnic groups.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transportadores de Anión Orgánico / Hígado Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Drug Metab Dispos Asunto de la revista: FARMACOLOGIA Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transportadores de Anión Orgánico / Hígado Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Drug Metab Dispos Asunto de la revista: FARMACOLOGIA Año: 2015 Tipo del documento: Article Pais de publicación: Estados Unidos