Genética Molecular, Redinren, and Fundación Renal, Hospital Universitario Central de Asturias, Oviedo, Spain.
Transplantation. 2009 Aug 15;88(3 Suppl):S62-7. doi: 10.1097/TP.0b013e3181afe9e7.
Cyclosporine A and tacrolimus (Tac) are inmunosuppresive drugs with a narrow therapeutic range. Underdosing is associated with organ rejection, whereas overdosing could result in toxicity. Therapeutic drug monitoring at different postdose times is necessary to maintain the blood concentrations within a target window. These calcineurin inhibitors are characterized by a broad interindividual pharmacokinetics variability, which makes the determination of the initial dose difficult. In a patient receiving a dose, the amount of the drug that is measured in the blood determines its bioavailability, which depends on the absorption, biotransformation, and elimination of the drug. These processes are primarily controlled by efflux pumps and enzymes of the cytochrome P (CYP) 450 family. DNA variants at the genes encoding these proteins contribute to the interindividual heterogeneity for calcineurin inhibitors metabolism. Cyclosporine A and Tac are metabolized by CYP3A4 and CYP3A5, and several single nucleotide polymorphisms in the two genes have been associated with differences in drug clearance. Carriers of the CYP3A5 wild-type allele have a higher CYP3A5 expression compared with individuals who are homozygous for a common DNA variant that affects gene splicing (CYP3A5*3). For renal transplant recipients receiving Tac, homozygotes for this nonexpression allele would exhibit significantly lower Tac clearance and may require a lower dose to remain within the blood target concentration compared with CYP3A5 expressors. To date, this CYP3A5 variant is the only reported genetic factor to predict the appropiate starting dosage of Tac, avoiding overdosing and improving the outcome of renal transplantation.
环孢素 A 和他克莫司（Tac）是具有窄治疗范围的免疫抑制剂。剂量不足与器官排斥有关，而剂量过大可能导致毒性。需要在不同的给药后时间进行治疗药物监测，以将血药浓度维持在目标范围内。这些钙调神经磷酸酶抑制剂的个体间药代动力学变异性很宽，这使得确定初始剂量变得困难。在接受剂量的患者中，血液中测量的药物量决定其生物利用度，这取决于药物的吸收、生物转化和消除。这些过程主要由外排泵和细胞色素 P（CYP）450 家族的酶控制。编码这些蛋白质的基因中的 DNA 变体导致钙调神经磷酸酶抑制剂代谢的个体间异质性。环孢素 A 和 Tac 由 CYP3A4 和 CYP3A5 代谢，这两个基因中的几个单核苷酸多态性与药物清除率的差异有关。与影响基因剪接的常见 DNA 变体（CYP3A5*3）纯合的个体相比，携带 CYP3A5 野生型等位基因的个体具有更高的 CYP3A5 表达。对于接受 Tac 的肾移植受者，该无表达等位基因的纯合子表现出明显较低的 Tac 清除率，并且与 CYP3A5 表达者相比，可能需要较低的剂量才能保持在血靶浓度内。迄今为止，这种 CYP3A5 变体是唯一报道的可预测 Tac 适当起始剂量的遗传因素，可避免剂量过大并改善肾移植的结果。
