College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea.
Eur J Clin Pharmacol. 2012 May;68(5):657-69. doi: 10.1007/s00228-011-1182-5. Epub 2011 Dec 20.
The purpose of this study was to characterize the effects of clinical and genetic variables on the pharmacokinetics and complications of tacrolimus during the first year after kidney transplantation.
One hundred and thirty-two Korean kidney recipients who received tacrolimus were genotyped for ABCB1 (exons 12, 21, and 26) and CYP3A5 (intron 3). Tacrolimus trough levels, dose, or dose-adjusted trough levels and complications were compared among patients during the early stage (3, 7, 14, 30, and 90 days) and up to 1 year according to the genotypes.
A donor source-adjusted linear mixed model with multilevel analysis adjusting for age, body weight, hematocrit, and serum creatinine showed that CYP3A5 genotype is associated with dose-adjusted level of tacrolimus (p < 0.001). The influence of ABCB1 polymorphisms on the pharmacokinetics or complications of tacrolimus was less certain in our study. The incidence of acute rejections was significantly higher in recipients of cadaveric donor kidney (p < 0.05).
A generalized estimating equation model analysis showed that alopecia and hyperlipidemia were associated with dose-adjusted level of tacrolimus (p < 0.001). Genotype of CYP3A5 variants along with significant clinical covariates may be useful in individualizing tacrolimus therapy in kidney transplantation patients.
本研究旨在探讨临床和遗传变量对肾移植后第一年他克莫司药代动力学和并发症的影响。
对 132 名接受他克莫司治疗的韩国肾移植受者进行 ABCB1（外显子 12、21 和 26）和 CYP3A5（内含子 3）的基因分型。根据基因型比较患者在早期（3、7、14、30 和 90 天）和 1 年内的他克莫司谷浓度、剂量或剂量调整后的谷浓度和并发症。
采用调整年龄、体重、红细胞压积和血清肌酐的供体来源调整线性混合模型进行多层次分析，结果表明 CYP3A5 基因型与他克莫司的剂量调整水平相关（p<0.001）。在本研究中，ABCB1 多态性对他克莫司药代动力学或并发症的影响不太确定。尸体供体肾移植受者的急性排斥反应发生率明显更高（p<0.05）。
广义估计方程模型分析表明，脱发和高血脂与他克莫司的剂量调整水平相关（p<0.001）。CYP3A5 变体的基因型以及显著的临床协变量可能有助于个体化肾移植患者的他克莫司治疗。
