Peng Kuan-wei, Bacon James, Zheng Ming, Guo Yingying, Wang Michael Zhuo
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.).
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.)
Drug Metab Dispos. 2015 Jul;43(7):1045-55. doi: 10.1124/dmd.115.063362. Epub 2015 Apr 29.
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.
肝脏有机阴离子转运多肽1B1、1B3和2B1以及P-糖蛋白在调节药物的肝脏摄取和胆汁排泄中发挥着重要作用。有人提出，OATP1B1介导的他汀类药物肝脏摄取的内在种族变异性是白种人和亚洲人之间他汀类药物血浆暴露量种族差异的基础。我们采用靶向定量蛋白质组学方法，测定了一组人类肝脏（n = 141）中OATP1B1、OATP1B3、OATP2B1、P-糖蛋白和PMCA4（一种管家蛋白）的肝脏蛋白浓度，并比较了白种人、亚洲人、非裔美国人及身份不明捐赠者之间的蛋白表达情况。使用包含脱氧胆酸钠作为膜蛋白增溶剂的优化方案，这些转运蛋白在所有肝脏中的肝脏蛋白表达水平（平均值±标准差）分别确定为15.0±6.0、16.1±8.1、4.1±1.3、0.6±0.2和2.4±1.0 fmol/μg总膜蛋白。换算系数为100 mg湿肝组织中含3.5 mg总膜蛋白。OATP1B1蛋白表达与c.388A>G（rs2306283，N130D）单核苷酸多态性显著相关。跨种族比较时，亚洲人肝脏中OATP1B1和OATP1B3的表达水平相对于白种人意外地更高，这表明仅肝脏OATP表达并不能解释亚洲人与白种人相比全身他汀类药物水平升高的现象。这些发现可能有助于改进基于生理学的药代动力学模型，以预测他汀类药物的药代动力学特征，并实现跨种族群体外推OATP底物的药代动力学数据。
