CYP3A4,CYP3A5和MDR1基因多态性对环孢素处置的影响

环孢素是一个广泛用于器官移植患者的免疫抑制剂,具有治疗指数窄,不同个体间药代动力学差异较大的特点。它主要通过肝脏和小肠的CYP3A4和CYP3A5代谢;同时它又是药物转运体的底物。不同个体间药物代谢酶和转运体活性的差异可能是造成不同器官移植患者环孢素药代动力学差异的主要原因。而遗传因素即编码药物代谢酶和转运体基因序列的差异可能是其产生活性差异的分子机制。因此,从编码药物代谢酶和转运体的基因入手,可能会为器官移植患者提供最优的治疗方案。

Contribution of genetic polymorphisms of the CYP3A4, CYP3A5 and MDR1 genes to cyclosporine disposition

Cyclosporine is an immunosuppressive drug largely used in organ transplantation.It is characterized by a narrow therapeutic index and wide interindividual variability in its pharmacokinetics. Cyclosporine is metabolized primarily by CYP3A4 and CYP3A5 in the liver and small intestine and also substrate for P-gp, encoded by MDR1. The interindividual heterogeneity in enzymatic activity of small intestine and liver CYP3A4 and CYP3A5, and intestine P-gp have contributed to oral cyclosporine pharmacokinetics in kidney, heart,liver and lung transplant patients. The differences in enzymatic activity of CYP3A and P-gp are believed to be due to CYP3A4, CYP3A5 and MDR1 genetic mutation. Therefore, a investigation which the effect of sequence variants in gene encoding drug-metabolizing enzymes and drug transporter to cyclosporine disposition may lead to individualized drug dosing and improved therapeutics.