CYP3A5和MDR1基因多态性对中国肝移植患者他克莫司药动学的影响

目的探讨细胞色素P450酶3A5（CYP3A5）基因和多药耐药基因（MDR1）C1236T、G2677T／A、C3435T多态性对肝移植患者口服他克莫司（TAC）后体内药动学参数的影响。方法采集28例肝移植患者手术后第1周和第3周血标本，采用LC—MS／MS法检测TAC血药浓度，计算主要药动学参数。采用聚合酶链反应结合基因测序分析28例肝移植患者CYP3A5＊3和MDR1主要基因型。结果携带MDR1 3435T基因型的肝移植患者口服TAC后，药动学参数AUC0→1和ρmax明显高于3435CC型患者，而CYP3A5＊3、MDR1 C1236T和G2677T／A基因多态性对TAC的药动学参数无明显影响。结论携带MDR1 3435T基因型肝移植患者比3435CC型患者需要较高剂量才能达到目标浓度。

Influence of genetic polymorphism of CYP3A5 and MDR1 on the pharmacokinetics of tacrolimus in Chinese liver transplantation patients

AIM To investigate the infltence of CYP3A5＊3 and MDR1 C1236T, G2677T/A and C3435T genotypes on tacrolimus （TAC） pharmacokinetics in Chinese liver transplant recipients. METHODS The blood samples of 28 patients were collected after 1 week and 3 weeks therapy of TAC after liver transplantation. The TAC concentration in whole blood was measured by LC-MS/MS. The pharmacokinetic parameters were calculated. Polymerase chain reaction and gene sequencing were used for CYP3A5 ＊ 3 and MDR1 genotyping in 28 patients. RESULTS The dose- and weight- adjusted peak concentration （ρmax） and area under the concentration-time curve （AUC0→1） were significantly higher in patients carrying MDRI 3435T allele than 3435CC patients. CYP3A5 ＊3, MDR1 C1236T and G2677T/A genotypes did not affect TAC pharmacokinetic parameters. CONCLUSION Liver transplant recipients with MDR1 3435CC may require higher dose of TAC than 3435T carriers.