Kuypers D R J, de Jonge H, Naesens M, Lerut E, Verbeke K, Vanrenterghem Y
Department of Nephrology and Renal Transplantation, University Hospitals of Leuven, Leuven, Belgium.
Clin Pharmacol Ther. 2007 Dec;82(6):711-25. doi: 10.1038/sj.clpt.6100216. Epub 2007 May 9.
The impact of CYP3A and MDR1 gene single-nucleotide polymorphisms on long-term tacrolimus disposition and drug-related toxicity has not been assessed. A study was performed in 95 genotyped recipients by measuring (12 and 4 h) concentration-time curves on day 7; 3, 6 months; 1, 2, 3, 4, and 5 years after transplantation. In contrast to recipients carrying the CYP3A41/CYP3A51 or CYP3A41B/CYP3A51 genotypes, dose-corrected tacrolimus exposure almost doubled over 5 years in patients with the CYP3A41/ CYP3A53 genotype (AUC(0-12 h): from 41.7+/-18.7 to 80+/-39.2 ng h/ml/mg; P<0.05), whereas apparent oral steady-state clearance and dose requirements significantly decreased accordingly. The CYP3A41/CYP3A51 and CYP3A41B/CYP3A51 genotypes were significantly more frequently associated with the development of biopsy-proven tacrolimus-related nephrotoxicity than the CYP3A41/ CYP3A53 genotype (37.5 vs 11.2%; P=0.03 and 42.8 vs 11.2%; P=0.02). The lack of a time-related increase in dose-corrected tacrolimus exposure observed with the CYP3A41/CYP3A51 and CYP3A41B/CYP3A51 genotypes is associated with tacrolimus-related nephrotoxicity, possibly as a result of higher concentrations of toxic metabolites.
细胞色素P450 3A（CYP3A）和多药耐药蛋白1（MDR1）基因单核苷酸多态性对他克莫司长期处置及药物相关毒性的影响尚未得到评估。对95名基因分型的受者进行了一项研究，通过测量移植后第7天、3个月、6个月、1年、2年、3年、4年和5年时（12小时和4小时）的浓度-时间曲线。与携带CYP3A41/CYP3A51或CYP3A41B/CYP3A51基因型的受者相比，携带CYP3A41/CYP3A53基因型的患者在5年期间剂量校正后的他克莫司暴露量几乎增加了一倍（药时曲线下面积（AUC(0 - 12 h)）：从41.7±18.7增至80±39.2 ng·h/ml/mg；P<0.05），而表观口服稳态清除率和剂量需求相应显著降低。与CYP3A41/CYP3A53基因型相比，CYP3A41/CYP3A51和CYP3A41B/CYP3A51基因型与经活检证实的他克莫司相关肾毒性的发生显著更频繁相关（分别为37.5%对11.2%；P = 0.03以及42.8%对11.2%；P = 0.02）。CYP3A41/CYP3A51和CYP3A41B/CYP3A51基因型未观察到剂量校正后的他克莫司暴露量随时间增加，这与他克莫司相关肾毒性有关，可能是由于有毒代谢物浓度较高所致。
