López-Montenegro Soria M A, Kanter Berga J, Beltrán Catalán S, Milara Payá J, Pallardó Mateu L M, Jiménez Torres N V
Department of Pharmacy, Dr Peset Universitary Hospital, and University of Valencia, Valencia, Spain.
Transplant Proc. 2010 Oct;42(8):3031-3. doi: 10.1016/j.transproceed.2010.08.001.
Genetic polymorphisms of metabolism enzymes or intestinal drug transporters may affect pharmacokinetic responses to immunosuppressive drugs in renal transplant recipients. We sought to identify the frequency of genetic polymorphisms and their importance for individualization of tacrolimus doses.
We performed an observational study in 35 renal transplant recipients treated with tacrolimus, mycophenolate mofetil, and corticosteroids. Tacrolimus concentrations were determined by immunoanalysis (IMx method; Abbott Diagnostics, Abbott Park, Ill), on 11 blood samples per patient during the first 6 weeks after renal transplantation. For each patient, we calculated the mean value and its standard error (SEM) of the concentration/dose ratio (ng/mL/mg) of tacrolimus. The pharmacogenetic analysis included single nucleotide polymorphisms (SNPs) in the CYP3A5 (CYP3A53 (A6986G), CYP3A56 (G14690A), MDR1 (C3435T and G2677T/A) and PXR (C-25385T) genes.
Of the patients, 62.8% (n=22) were men and the overall mean age was 55 years (95% confidence interval, 48.7-62.7). The SNP distribution was: CYP3A53: G/G=82.9%, A/G=17.1%; CYP3A56: G/G=88.6%, G/A=11.4%; MDR1 C3435T: C/C=25.7%, C/T=62.9%, T/T=11.4%; for MDR1 G2677T/A: G/G=22.9%, G/T=65.7%, T/T=11.4% and for PXR: C/T=85.7%, T/T=14.3%. Tacrolimus concentration/dose ratios in heterozygote patients for CYP3A53 genotypes was >120% lower than for the homozygote CYP3A53 genotype (0.65±0.04 vs 1.45±0.05; P<.0001). Wild-type MDR1 (3435 C/C) genotype patients showed up to 40% lower concentration/dose ratios compared with heterozygote and homozygote genotypes (C/C; 1±0.07 vs C/T; 1.4±0.06 vs T/T; 1.37±0.09; P<.0001).
Intestinal absorption and metabolism of tacrolimus was significantly affected by the SNPs in the CYP3A5 and MDR1 genes, which may offer a useful tool to optimize tacrolimus dosing after renal transplantation.
代谢酶或肠道药物转运体的基因多态性可能影响肾移植受者对免疫抑制药物的药代动力学反应。我们试图确定基因多态性的频率及其对他克莫司剂量个体化的重要性。
我们对35例接受他克莫司、霉酚酸酯和皮质类固醇治疗的肾移植受者进行了一项观察性研究。肾移植后的前6周内，每位患者采集11份血样，采用免疫分析方法（IMx法；雅培诊断公司，伊利诺伊州雅培公园）测定他克莫司浓度。对于每位患者，我们计算了他克莫司浓度/剂量比（ng/mL/mg）的平均值及其标准误（SEM）。药物遗传学分析包括CYP3A5（CYP3A53（A6986G）、CYP3A56（G14690A））、MDR1（C3435T和G2677T/A）和PXR（C-25385T）基因的单核苷酸多态性（SNP）。
患者中，62.8%（n=22）为男性，总体平均年龄为55岁（95%置信区间，48.7-62.7）。SNP分布情况为：CYP3A53：G/G=82.9%，A/G=17.1%；CYP3A56：G/G=88.6%，G/A=11.4%；MDR1 C3435T：C/C=25.7%，C/T=62.9%，T/T=11.4%；MDR1 G2677T/A：G/G=22.9%，G/T=65.7%，T/T=11.4%；PXR：C/T=85.7%，T/T=14.3%。CYP3A53基因型杂合子患者的他克莫司浓度/剂量比低于CYP3A53基因型纯合子患者120%以上（0.65±0.04对1.45±0.05；P<0.0001）。野生型MDR1（3435 C/C）基因型患者的浓度/剂量比与杂合子和纯合子基因型相比低达40%（C/C；1±0.07对C/T；1.4±0.06对T/T；1.37±0.09；P<0.0001）。
CYP3A5和MDR1基因中的SNP对他克莫司的肠道吸收和代谢有显著影响，这可能为优化肾移植后他克莫司的给药提供一个有用的工具。
