Provenzani Alessio, Notarbartolo Monica, Labbozzetta Manuela, Poma Paola, Biondi Filippo, Sanguedolce Rosario, Vizzini Giovanni, Palazzo Ugo, Polidori Piera, Triolo Fabio, Gridelli Bruno, D'Alessandro Natale
Department of Clinical Pharmacy, ISMETT, Palermo, Italy.
Ann Transplant. 2009 Jan-Mar;14(1):23-31.
Tacrolimus is a substrate of cytochrome P-450 (CYP) 3A enzyme and of the drug transporter ABCB1. We have investigated the effects of possible relevant CYP3A5 and ABCB1 single nucleotide polymorphisms (SNPs) present in both donors and recipients on tacrolimus blood levels achieved in a population of 32 Caucasian liver transplant patients.
MATERIAL/METHODS: At 1, 3 and 6 months after transplantation, tacrolimus doses (mg/kg/day) and trough blood levels (C(0)) were determined. Polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for genotyping CYP3A5*3 [6986A>G] as well as ABCB1 at exons 21 [2677G>T] and 26 [3435C>T].
87.5% of the population showed a CYP3A5*3/*3 genotype. For the ABCB1 SNPs, in the case of 3435C>T the total frequency observed for the allelic variant was 50%. For the 2677G>T, the total frequency of the allelic variant was 12.5%, lower than in other Caucasian populations and without any significant linkage with 3435C>T. At 3 and 6 months after transplantation, tacrolimus dose requirements were significantly higher in patients receiving a liver with one copy of the *1 allele compared to those homozygous for the *3 allele (0.111+/-0.057 vs. 0.057+/-0.030 [P<0.05] at 3 month and 0.086+/-0.051 vs. 0.044+/-0.025 [P<0.05] at 6 month). For the recipients' genotypes, the presence of at least one *1 copy tended, though not statistically significantly, to increase tacrolimus doses. With regard to the ABCB1 SNPs, they did not show any influence on tacrolimus dosing requirements.
Pharmacogenetic analysis of CYP3A5 in the donor could contribute to determine the appropriate initial dosage of tacrolimus in liver transplant patients.
他克莫司是细胞色素P-450（CYP）3A酶和药物转运体ABCB1的底物。我们研究了供体和受体中可能存在的相关CYP3A5和ABCB1单核苷酸多态性（SNP）对32例白种人肝移植患者群体中他克莫司血药浓度的影响。
材料/方法：在移植后1、3和6个月，测定他克莫司剂量（mg/kg/天）和谷浓度血药水平（C(0)）。采用聚合酶链反应后接限制性片段长度多态性分析对CYP3A5*3 [6986A>G]以及ABCB1基因第21外显子[2677G>T]和第26外显子[3435C>T]进行基因分型。
87.5%的人群表现为CYP3A53/3基因型。对于ABCB1单核苷酸多态性，在3435C>T的情况下，观察到的等位基因变异总频率为50%。对于2677G>T，等位基因变异总频率为12.5%，低于其他白种人群体，且与3435C>T无显著连锁关系。在移植后3个月和6个月，接受带有一个1等位基因拷贝肝脏的患者与3等位基因纯合子患者相比，他克莫司剂量需求显著更高（3个月时为0.111±0.057对0.057±0.030 [P<0.05]，6个月时为0.086±0.051对0.044±0.025 [P<0.05]）。对于受体基因型，至少存在一个*1拷贝虽无统计学显著差异，但有增加他克莫司剂量的趋势。关于ABCB1单核苷酸多态性，它们对他克莫司给药需求未显示任何影响。
对供体CYP3A5进行药物遗传学分析有助于确定肝移植患者他克莫司的合适初始剂量。
