EFFECTS OF GENETIC POLYMORPHISMS OF CYP3A4 , CYP3A5 AND MDR1 ON CYCLOSPORINE PHARMACOKINETICS AFTER RENAL TRANSPLANTATION

作者：HU Yong-fang, Wen Qiu, Zhaoqian Liu, Li‐Jun Zhu, Zhong‐Qi Liu, Jianghua Tu, Dan Wang, Zhi Li, Jun He, Gan‐Ping Zhong, Gan Zhou, Hong‐Hao Zhou · 发表于：Clinical and Experimental Pharmacology and Physiology · 年份：2006 · DOI：10.1111/j.1440-1681.2006.04492.x · 被引用次数：95 · 研究领域：Drug Transport and Resistance Mechanisms、Renal Transplantation Outcomes and Treatments、Pharmacological Effects and Toxicity Studies

1. The calcineurin inhibitor cyclosporine is widely used to prevent allograft rejection after solid organ transplantation. It has a narrow therapeutic index and shows considerable interindividual differences in its pharmacokinetics. Interindividual differences in the activity and expression of the metabolising enzymes cytochrome P450 (CYP) 3A4 and 3A5 and the multidrug efflux pump P-glycoprotein (P-gp) contribute considerably to cyclosporine pharmacokinetics. Variability in the activity of CYP3A4, CYP3A5 and P-gp could be considered to result from genetic polymorphisms encoding their genes. 2. The aim of the present study was to evaluate retrospectively the effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine dose adjusted trough blood concentration during the early period after renal transplantation in Chinese patients. 3. One hundred and six renal transplant recipients in China were genotyped by polymerase chain reaction-restriction fragment length polymorphism for CYP3A4*18A, CYP3A5*3 and MDR1 C3435T. Cyclosporine whole blood levels were measured by fluorescence polarization immunoassay. Dose-adjusted trough blood concentrations (C(0)) were determined and compared among the different genotype groups. 4. The frequency of the CYP3A4*18A, CYP3A5*3 and MDR1 C3435T variant alleles were 0.005 (95% confidence interval (CI) 0.048, 0.0049), 0.783 (95% CI 0.781, 0.785) and 0.528 (95% CI 0.526, 0.531), respectively, and these alleles exhibited incomplete linkag...