Mendes J, Martinho A, Simoes O, Mota A, Breitenfeld L, Pais L
Centro de Histocompatibilidade do Centro, Coimbra, Portugal.
Transplant Proc. 2009 Apr;41(3):840-2. doi: 10.1016/j.transproceed.2009.01.050.
Immunosuppressive drugs, such as tacrolimus (FK506) and cyclosporine (CsA), play an essential role in graft survival, preventing rejection. Large interindividual differences in drug-metabolizing enzymes as well as in drug transporters make the task of reaching the optimal concentrations difficult. The bioavailability of CsA and FK506 seems to be associated with the cytocrhome P450 IIIA (CYP3A) gene. It has also been described that the Multi Drug Resistance 1 (MDR1) gene that encodes for polyglycoprotein-P (P-gp) may influence the metabolizing action of FK506 and CsA. Therefore, we sought, to correlate single nucleotide polymorphisms (SNPs) in the CYP3A and MDR1 genes with the concentrations of FK506 and CsA. For this purpose we analyzed 2 groups of renal transplant recipients by sequencing: one receiving a CsA immunosuppressive regime, and other, an FK506-immunosuppression. This study showed that subjects in the FK506 group who had encoded the 1236C>T substitution in the MDR1 gene displayed 44.4% higher drug concentrations compared with ("wild-type") individuals. Individuals carrying the 2677G>T,A mutation showed FK506 concentrations that were 44.7% higher than the wild-type individuals. Concerning the CsA group, individuals carrying the 22915A>C substitution displayed CsA concentrations 52.1% higher than wild-type individuals.
免疫抑制药物，如他克莫司（FK506）和环孢素（CsA），在移植物存活及预防排斥反应中发挥着至关重要的作用。药物代谢酶以及药物转运体存在较大的个体差异，这使得达到最佳浓度变得困难。CsA和FK506的生物利用度似乎与细胞色素P450 IIIA（CYP3A）基因相关。也有描述称，编码多药耐药蛋白1（P - gp）的多药耐药基因1（MDR1）可能会影响FK506和CsA的代谢作用。因此，我们试图将CYP3A和MDR1基因中的单核苷酸多态性（SNP）与FK506和CsA的浓度相关联。为此，我们通过测序分析了两组肾移植受者：一组接受CsA免疫抑制方案，另一组接受FK506免疫抑制方案。这项研究表明，FK506组中在MDR1基因编码了1236C>T替换的受试者，其药物浓度比（“野生型”）个体高44.4%。携带2677G>T、A突变的个体显示FK506浓度比野生型个体高44.7%。对于CsA组，携带22915A>C替换的个体显示CsA浓度比野生型个体高52.1%。
