Roy Jean Nicholas, Barama Azemi, Poirier Charles, Vinet Bernard, Roger Michel
Laboratoire d'immunogénétique, Centre hospitalier de l'Université de Montréal (CHUM)-Hôpital Notre-Dame, Montreal, Quebec, Canada.
Pharmacogenet Genomics. 2006 Sep;16(9):659-65. doi: 10.1097/01.fpc.0000220571.20961.dd.
The immunosuppressive drug tacrolimus requires strict therapeutic monitoring due to its narrow therapeutic index and great inter-individual variability. Cytochrome P450 3A4 (Cyp3A4) and Cyp3A5 are the most important contributors to tacrolimus metabolism while the P-glycoprotein pump (MDR-1) modulates its bioavailability. The objective was to investigate the association between Cyp3A4, Cyp3A5, and MDR-1 polymorphisms and tacrolimus pharmacokinetics in the early period after renal transplantation.
Forty-four renal transplant recipients were genotyped for 8 Cyp3A4, 7 Cyp3A5, and 5 MDR-1 genetic variants affecting the proteins' expression and/or function. Dose-adjusted tacrolimus though levels were determined during the first week after transplantation and correlated with corresponding genotype.
We found no correlation between Cyp3A4 polymorphism and tacrolimus pharmacokinetics. Patients who do not carry both Cyp3A53 alleles achieved lower mean dose-adjusted tacrolimus blood concentrations (p<0.001) and needed a longer time to reach the target concentration (10-12 ng/ml; p<0.001) compared to Cyp3A53 homozygotes. Patients with less than three copies of MDR-1 (T-129C, C3435T and G2677T) polymorphisms, associated with reduced expression of P-glycoprotein, had also lower dose-adjusted tacrolimus blood concentrations compared to patients having equal to or greater than three copies of MDR-1 genetic variants (P=0.003). There was no difference in the rate of biopsy-confirmed acute rejection among groups during the first 3 months after transplantation.
The complete absence of Cyp3A5*3 allele and the accumulation of less than three copies of MDR-1 (T-129C, C3435T and G2677T) polymorphisms are associated with lower tacrolimus blood levels identifying these genotypes as markers for patients requiring higher tacrolimus doses.
免疫抑制药物他克莫司因其治疗指数窄且个体间差异大，需要严格的治疗监测。细胞色素P450 3A4（Cyp3A4）和Cyp3A5是他克莫司代谢的最重要贡献者，而P-糖蛋白泵（MDR-1）调节其生物利用度。目的是研究肾移植术后早期Cyp3A4、Cyp3A5和MDR-1基因多态性与他克莫司药代动力学之间的关联。
对44例肾移植受者进行基因分型，检测影响蛋白质表达和/或功能的8种Cyp3A4、7种Cyp3A5和5种MDR-1基因变异。在移植后第一周测定剂量调整后的他克莫司血药浓度，并与相应基因型进行关联分析。
我们发现Cyp3A4基因多态性与他克莫司药代动力学之间无相关性。与Cyp3A53纯合子相比，未携带两个Cyp3A53等位基因的患者平均剂量调整后的他克莫司血药浓度较低（p<0.001），且达到目标浓度（10-12 ng/ml）所需时间更长（p<0.001）。MDR-1（T-129C、C3435T和G2677T）基因多态性与P-糖蛋白表达降低相关，拷贝数少于三个的患者与拷贝数等于或多于三个的患者相比，剂量调整后的他克莫司血药浓度也较低（P=0.003）。移植后前3个月各基因型组活检确诊的急性排斥反应发生率无差异。
完全不存在Cyp3A5*3等位基因以及MDR-1（T-129C、C3435T和G2677T）基因多态性拷贝数少于三个与他克莫司血药浓度较低相关，这些基因型可作为需要更高他克莫司剂量患者的标志物。
