Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
Clin Pharmacol Ther. 2013 Mar;93(3):275-82. doi: 10.1038/clpt.2012.261. Epub 2012 Dec 27.
Individual variability in expression and function of organic anion-transporting polypeptide 1B1 (OATP1B1), multidrug resistance protein 1 (MDR1), and/or cytochrome P450 3A4 (CYP3A4) may impact the clinical response of many drugs. We investigated the correlation between expression of these proteins and pharmacokinetics of atorvastatin, a substrate of all three, in 21 obese patients with paired biopsies from liver and intestinal segments. The patients were also screened for the SLCO1B1 c.521T→C variant alleles. Approximately 30% (r(2) = 0.28) of the variation in oral clearance (CL/F) of atorvastatin was explained by hepatic OATP1B1 protein expression (P = 0.041). Patients carrying the SLCO1B1 c.521C variant allele (homozygous, n = 4; heterozygous, n = 2) exhibited 45% lower CL/F of atorvastatin than the c.521TT carriers (P = 0.067). No association between hepatic and intestinal expression of MDR1 or CYP3A4 and atorvastatin pharmacokinetics was found (P > 0.149). In conclusion, this study suggests that OATP1B1 phenotype is more important than CYP3A4 and MDR1 phenotypes for the individual pharmacokinetic variability of atorvastatin.
个体在有机阴离子转运多肽 1B1（OATP1B1）、多药耐药蛋白 1（MDR1）和/或细胞色素 P4503A4（CYP3A4）表达和功能上的差异可能会影响许多药物的临床反应。我们研究了 21 名肥胖患者肝脏和肠道段配对活检中这些蛋白表达与阿托伐他汀药代动力学之间的相关性，阿托伐他汀是这三种蛋白的底物。这些患者还接受了 SLCO1B1 c.521T→C 变异等位基因的筛查。阿托伐他汀口服清除率（CL/F）的约 30%（r(2) = 0.28）可由肝脏 OATP1B1 蛋白表达来解释（P = 0.041）。携带 SLCO1B1 c.521C 变异等位基因（纯合子，n = 4；杂合子，n = 2）的患者比 c.521TT 携带者的阿托伐他汀 CL/F 低 45%（P = 0.067）。未发现肝脏和肠道 MDR1 或 CYP3A4 表达与阿托伐他汀药代动力学之间存在关联（P > 0.149）。总之，这项研究表明，对于阿托伐他汀的个体药代动力学变异性，OATP1B1 表型比 CYP3A4 和 MDR1 表型更为重要。
