肾移植患者中伏立康唑对他克莫司药代动力学的影响

Effects of voriconazole on pharmacokinetics of tacrolimus in renal transplantation patients

目的 探讨肾移植患者口服伏立康唑(VRC)对他克莫司(TAC)药代动力学的影响。方法 纳入在服用VRC前均已口服TAC超过2 d并达到稳态血药浓度的肾移植患者为研究对象,在服用VRC 200或400 mg·d^(-1)后的第3、5和10天,用高效液相色谱方法测定TAC的药物谷浓度(C_(0)),用聚合酶链反应法检测基因型,并比较联合使用VRC后TAC药代动力学的变化情况。结果 11例肾移植患者使用VRC后,TAC C_(0)为3~8μg·L^(-1),浓度剂量为原剂量的50.00%~87.50%。VRC对TAC的影响程度在个体间存在明显差异。在服用VRC后的TAC C_(0)平均值明显高于VRC前[(12.14±3.89)vs(5.20±2.79)μg·L^(-1)]。11例肾移植患者根据细胞色素P450(CYP)2C19-CYP3A5基因多态性进行分组,在联合用药情况下,慢代谢组TAC在第3、5和10天的C_(0)/剂量均显著高于快代谢组[(582.10±252.30)vs(439.03±166.08),(873.71±449.22)vs(666.60±168.00),(852.10±505.73)vs(261.50±81.98)μg·L^(-1)·mg^(-1)·kg;均P<0.01]。结论 肾移植患者口服VRC对TAC药代动力学有着显著的影响,两者联合应用TAC剂量需要减少原始剂量1/3的原则已经不适用,可能与VRC本身的药代动力学以及CYP2C19/CYP3A5基因多态性有关,建议在联合使用VRC和TAC时定期监测TAC药物浓度。

Objective To explore the effects of oral voriconazole(VRC) on the pharmacokinetics of tacrolimus(TAC) in renal transplant patients.Methods Renal transplant patients who had taken TAC orally for more than 2 days and achieved steady-state plasma concentration before taking VRC.The trough concentration of TAC was measured on the 3rd,5th and 10th days after VRC 200 or 400 mg · d^(-1)administration.The trough concentration(C_0) of TAC was determined by high performance liquid chromatography.The genotypes of TAC were determined by polymerase chain reaction and the pharmacokinetics of TAC after combined use of VRC were compared.Results After the use of VRC,the TAC C_(0) of 11 renal transplant patients was 3-8 μg·L^(-1),and the concentration of TAC ranged from 50.00% to 87.50% of the original dose.Additionally,the impact of VRC on TAC varied significantly among individuals.The mean TAC C_(0) value after VRC administration was significantly higher than the value before VRC[(12.14±3.89) vs(5.20±2.79) μg · L^(-1)].Eleven renal transplant patients were grouped according to cytochrome P450(CYP) 2C19-CYP3A5 gene polymorphism,under the condition of combined administration,the C_0/dose of TAC in the slow metabolizer group was higher than that in the fast metabolizer group on the 3rd,5th and 10th days[(582.10±252.30) vs(439.03±166.08),(873.71±449.22) vs(666.60±168.00),(852.10±505.73) vs(261.50±81.98) μg · L^(-1)·mg^(-1)·kg;all P <0.01].Conclusion TAC pharmacokinetics was significantly affected by the VRC in renal transplant recipients,and the principle that TAC dose needed to be reduced by one-third of the original dose was no longer applicable,which may be related to the pharmacokinetics of the VRC itself and the gene polymorphism of CYP2C19/CYP3A5 enzyme.It is recommended to regularly monitor the concentration of TAC when VRC and TAC are used in combination.