【作者】 杨艺红；

【导师】 肖志坚；

【作者基本信息】 中国协和医科大学 ， 内科学， 2008， 博士

【摘要】 【目的】探讨MDR1及CYP3A5基因多态性对再生障碍性贫血（aplasticanemia,AA）患者环孢菌素A（cyclosporine A,CsA）血药浓度的影响。【方法】选取达目标浓度范围[CsA谷浓度＞150ng/ml或服药后2h血药浓度＞600ng/ml]的AA患者99例,用聚合酶链反应-限制性内切酶片断长度多态性（PCR-RFLP）方法分析MDR1 C1236T、G2677T/A、C3435T和CYP3A5木3基因型。比较各基因型及单倍体型CsA剂量调整的谷浓度[谷浓度（C₀）/（剂量/体重）,C₀t]和CsA剂量调整的服药后2h血药浓度[服药后2h血药浓度（C₂）/（剂量/体重）,C₂t]的差异。【结果】MDR1 1236C等位基因频率为37.9%,MDR1 1236T等位基因频率为62.1%;MDR1 2677G、2677T和2677A等位基因频率分别为43.5%、40.8%和15.7%;MDR1 3435C和3435T等位基因频率分别为62.7%和37.3%;CYP3A5*1等位基因频率26.3%,CYP3A5*3等位基因频率73.7%。CYP3A5*3/*3基因型和CYP3A5*1/*1（或CYP3A5*1/*3）基因型C₂t中位数分别为202.59（58.25-418.28）和165.88（88.49-2.88.01）ng/ml/（mg/kg）,具有显著性差异（P＜0.05）,示CYP3A5*3变异型纯合子个体C₂t高于野生型纯合子和杂合子。CYP3A5*1/*1（或CYP3A5*1/*3）与CYP3A5*3/*3基因型C₀t比较,差别无统计学意义（P＞0.05）。MDR1 C1236T、G2677T/A和C3435T各基因型及单倍体型C₀t和C₂t无显著性差异（P＞0.05）。【结论】AA患者CYP3A5*3单核苷酸多态性影响CsA药物代谢,是造成个体CsA生物利用度变异性程度大的原因之一。与携有CYP3A5*1等位基因的AA患者相比,CYP3A5*3/*3基因型患者口服较低的CsA剂量就能达到相当的C₂水平。更多还原

【Abstract】 ObjectiveThe study was aimed at investigating MDR-1 and CYP3A5 genetic polymorphisms effecting on cyclosporine（CsA） blood concentrations in aplastic anemia（AA） patients.Methods99 AA cases,reaching the target CsA blood concentrations[CsA trough blood concentrations（C₀） more than 150ng/ml or the peak concentrations 2h after oral ingestion（C₂） more than 600ng/ml],were genotyped by polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） for MDR1 C1236T,G2677T/A,C3435T and CYP3A5^*3. Dose-adjusted C₀ and C₂ were performed to analyze compared among the different genotype groups.ResultsAllele frequencies for C and T at position 1236 of MDR1 were 37.9% and 62.1%,respectively.For the single-nucleotide polymorphisms（SNPs） in MDR1 G2677T/A,the frequencies of the wildtype（G） and two other alleles（T/A） were found at allele frequencies of 43.5%,40.8%and 15.7%, respectively.The frequencies for C and T at position 3435 of MDR1 were 62.7%and 37.3%,respectively.For the CYP3A5 gene,the frequencies of CYP3A5^*1 and CYP3A5^*3 were 26.3%and 73.7%,respectively.The dose-adjusted C₂ in CYP3A5^*3/^*3 patients was larger than that of CYP3A5^*1/^*1 or CYP3A5^*1/^*3 patients[202.59（58.25-418.28） versus 165.88（88.49-288.01） ng/ml/（mg/kg）,P＜0.05].No significant difference in cyclosporine dose-adjusted C₀ and C₂ was observed in other genotypes and haplotypes.ConclusionSingle-nucleotide polymorphisms in CYP3A5^*3 have influence on the cyclosporine blood concentrations and be responsible,in part,for the large interindividual variability of cyclosporine pharmacokinetics in AA patient.Patients with the CYP3A5^*3/^*3 genotype require a low dose of cyclosporine to reach target C₂ levels.compared with those with the CYP3A5^*1 allele.更多还原