Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus
Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus
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DOI：
10.1016/s0009-9236(03)00168-1
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发表时间：
2003-09-01
影响因子：
6.7
通讯作者：
van Gelder, T
中科院分区：
文献类型：
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作者：
Hesselink, DA;van Schaik, RHN;van Gelder, T
背景钙调磷酸酶抑制剂环孢素（INN，环孢素）和他克莫司治疗指数较窄，药代动力学个体间差异较大。钙调磷酸酶抑制剂的口服生物利用度低被认为是由于代谢酶细胞色素P450（CYP 3A 4）和CYP 3A 5和多药外排泵P-糖蛋白，MDR-L.Objective编码的行动：我们的目的是确定CYP 3A 4，CYP 3A 5和MDR-1基因多态性的作用，在环孢素和他克莫司药代动力学个体间变异。对接受环孢素（n = 110）或他克莫司（n = 64）的肾移植受者进行CYP 3A 4 *1B和 *3、CYP 3A 5 *3和 *6以及MDR-1 C3435 T基因分型。结果：CYP 3A 5 *3/*3患者（n = 45）的他克莫司剂量调整谷浓度高于 *1/*3加 *1/*1患者（n = 17），如下所示：中位数和范围为94（34-398）ng/mL/mg/kg对比61（37-163）ng/mL/mg/kg（P < .0001，Mann-Whitney检验）。CYP 3A 4 *1B等位基因携带者（n = 10）的他克莫司剂量调整谷浓度低于野生型（*1/*I）基因型患者（n = 54）：中位数和范围分别为57（40-163）ng/mL/mg/kg和89（34-398）ng/mL/mg/kg）（P = 0.003，Mann-Whitney检验）。没有发现证据支持MDR-1 C3435 T多态性在他克莫司剂量需求中的作用。没有研究的多态性与环孢素剂量调整的predose concentration.Conclusion：作为一个组，与CYP 3A 5 *3/*3基因型的患者需要较少的他克莫司达到目标的predose浓度相比，CYP 3A 5 *1等位基因载体，而CYP 3A 4 *1B载体需要更多的他克莫司达到目标谷浓度相比，CYP 3A 4 *1纯合子。
Background The calcineurin inhibitors cyclosporine (INN, ciclosporin) and tacrolimus have a narrow therapeutic index and show considerable interindividual variability in their pharmacokinetics. The low oral bioavailability of calcineurin inhibitors is thought to result from the actions of the metabolizing enzymes cytochrome P450 (CYP) 3A4 and CYP3A5 and the multidrug efflux pump P-glycoprotein, encoded by MDR-L.Objective: Our objective was to determine the role of genetic polymorphisms in CYP3A4, CYP3A5, and MDR-1 with respect to interindividual variability in cyclosporine and tacrolimus pharmacokinetics.Methods. Kidney transplant recipients receiving cyclosporine (n = 110) or tacrolimus (n = 64) were genotyped for CYP3A4*1B and *3, CYP3A5*3 and *6, and MDR-1 C3435T. Dose-adjusted trough levels were determined and correlated with the corresponding genotype.Results: Tacrolimus dose-adjusted trough levels were higher in CYP3A5*3/*3 patients (n = 45) than in *1/*3 plus *1/*1 patients (n = 17), as follows: median and range, 94 (34-398) ng/mL per mg/kg versus 61 (37-163) ng/mL per mg/kg (P < .0001, Mann-Whitney test). CYP3A4*1B allele carriers (n = 10) had lower tacrolimus dose-adjusted trough levels compared with those in patients with the wild-type ( *1/*I) genotype (n = 54): median and range, 57 (40-163) ng/mL per mg/kg versus 89 (34-398) ng/mL per mg/kg) (P = .003, Mann-Whitney test). No evidence was found supporting a role for the MDR-1 C3435T polymorphism in tacrolimus dose requirement. None of the polymorphisms studied correlated with cyclosporine dose-adjusted predose concentrations.Conclusion: As a group, patients with the CYP3A5*3/*3 genotype require less tacrolimus to reach target predose concentrations compared with CYP3A5*1 allele carriers, whereas CYP3A4 *1B carriers require more tacrolimus to reach target trough concentrations compared with CYP3A4*1 homozygotes.