Hesselink Dennis A, van Schaik Ron H N, van der Heiden Ilse P, van der Werf Marloes, Gregoor Peter J H Smak, Lindemans Jan, Weimar Willem, van Gelder Teun
Department of Internal Medicine, Renal Tranplant Unit, Erasmus Medical Center, Rotterdam, The Netherlands.
Clin Pharmacol Ther. 2003 Sep;74(3):245-54. doi: 10.1016/S0009-9236(03)00168-1.
The calcineurin inhibitors cyclosporine (INN, cyclosporin) 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-1.
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.
Kidney transplant recipients receiving cyclosporine (n = 110) or tacrolimus (n = 64) were genotyped for CYP3A4*1B and 3, CYP3A53 and *6, and MDR-1 C3435T. Dose-adjusted trough levels were determined and correlated with the corresponding genotype.
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). CYP3A41B allele carriers (n = 10) had lower tacrolimus dose-adjusted trough levels compared with those in patients with the wild-type (*1/*1) 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.
As a group, patients with the CYP3A53/3 genotype require less tacrolimus to reach target predose concentrations compared with CYP3A51 allele carriers, whereas CYP3A41B carriers require more tacrolimus to reach target trough concentrations compared with CYP3A4*1 homozygotes.
钙调神经磷酸酶抑制剂环孢素（国际非专利药品名称，环孢菌素）和他克莫司的治疗指数较窄，其药代动力学存在显著的个体间差异。钙调神经磷酸酶抑制剂口服生物利用度低被认为是由代谢酶细胞色素P450（CYP）3A4和CYP3A5以及由多药耐药基因1（MDR-1）编码的多药外排泵P-糖蛋白的作用导致的。
我们的目的是确定CYP3A4、CYP3A5和MDR-1基因多态性在环孢素和他克莫司药代动力学个体间差异方面的作用。
对接受环孢素（n = 110）或他克莫司（n = 64）治疗的肾移植受者进行CYP3A41B和3、CYP3A53和6以及MDR-1 C3435T基因分型。测定剂量调整后的谷浓度，并将其与相应基因型进行关联分析。
CYP3A5*3/3基因型患者（n = 45）的他克莫司剂量调整后谷浓度高于1/3加1/*1基因型患者（n = 17），具体如下：中位数及范围，每毫克/千克体重94（34 - 398）纳克/毫升对61（37 - 163）纳克/毫升（P <.0001，曼-惠特尼检验）。与野生型（*1/1）基因型患者（n = 54）相比，CYP3A41B等位基因携带者（n = 10）的他克莫司剂量调整后谷浓度较低：中位数及范围，每毫克/千克体重57（40 - 163）纳克/毫升对89（34 - 398）纳克/毫升（P =.003，曼-惠特尼检验）。未发现证据支持MDR-1 C3435T多态性在他克莫司剂量需求方面的作用。所研究的多态性均与环孢素剂量调整后的给药前浓度无关。
总体而言，与CYP3A51等位基因携带者相比，CYP3A53/3基因型患者达到目标给药前浓度所需的他克莫司较少，而与CYP3A41纯合子相比，CYP3A4*1B携带者达到目标谷浓度所需的他克莫司较多。
