Effects MDR-1 And CYP3A5 Genetic Polymorphisms On Cyclosporine Blood Concentrations In Aplastic Anemia Patients

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.