Ethnic variability in the expression of hepatic drug transporters: absolute quantification by an optimized targeted quantitative proteomic approach.
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.
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.).
Kuan-wei
KW
Peng
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.).
James
J
Bacon
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.).
Ming
M
Zheng
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.).
Yingying
Y
Guo
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.
Michael Zhuo
MZ
Wang
D001741:Black or African American; D044466:Asian People; D002851:Chromatography, High Pressure Liquid; D003840:Deoxycholic Acid / Q000494:pharmacology; D005006:Ethnicity; D005838:Genotype; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000096:biosynthesis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040901:Proteomics; D044465:White People
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D027361:Organic Anion Transporters; D003840:Deoxycholic Acid; D053499:Plasma Membrane Calcium-Transporting ATPases