Effects Of MDR1,CYP3A4 And CYP3A5 Polymorphisms With Cyclosporine Blood Concentrations In Chinese Hematological System Disease Patients

ObjectiveThe objective of this study was to retrospectively evaluate the effects of MDR1,CYP3A4 and CYP3A5 genetic polymorphisms on cyclosporine A (CsA) blood concentrations in Chinese Hematological system disease patients.MethodsA total of 108 Hematological system disease patients receiving CsA were genotyped for MDR1 (C1236T, G2677T/A and C3435T), CYP3A4*18B and CYP3A5*3 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The trough blood concentrations of CsA (C0) were determined by fluorescence polarization immunoassay and their relationships with corresponding genotypes and haplotypes were investigated.ResultsAllele frequencies for C and T at position 1236 of MDR1 were 32%and 68%, 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 35%,47%and 18%, respectively. Allele frequencies for C and T at position 3435 of MDR1 were 62%and 38%, respectively. For the CYP3A4 gene, the frequencies of CYP3A4*1 and CYP3A4*18B were 75%and 25%, respectively. The frequencies of CYP3A5*1 and CYP3A5*3 were 25%and 75%, respectively. No significant difference in CsA Coin MDR1 C1236T and CYP3A4 genotypes (P>0.05). Patients with genotype 3435TT was 227.51±218.98 (ng/mL), which was higher than 3435CC and 3435CT (P<0.05). The Co in G2677T/A, TT/AA/TA variant genotypes was larger than GT/GA heterozygote genotypes [193.55±189.40 versus 120.71±72.99 (ng/mL), P<0.05]. Significant difference with the other genotypes, the Co in CYP3A5*3/*3 patients was 115.89±120.00 (ng/mL), P<0.05. Considered to dose-adjusted Co, patients with genotype 3435TT was 47.51±36.53 (ng/mL per mg/kg), which was significant difference with wildtype genotype and heterozygote genotype, P<0.05. The dose-adjusted Co in CYP3A4*1/*1 patients was larger than that of CYP3A4*18B/*18B patients (41.27±27.84 versus 21.35±13.43) ng/mL per mg/kg, P<0.05. The dose-adjusted Coin CYP3A5*3/*3 patients was 30.77±21.77 (ng/mL per mg/kg), which was significant difference than that of the other genotypes, P<0.05. There was a significant difference between 1236TT and 1236CT patients in Co who were CYP3A4*18B producers (152.73±133.24 versus 87.81±56.99) ng/mL, P<0.05. The Co and dose-adjusted Coin 1236TT,3435CC and 2677GT/GA patients, who were CYP3A5*3/*3 nonproducers, were larger than that of patients who were CYP3A5*1 producers, P<0.05. The Co in 3435TT and 2677TT/AA/AT patients were higher than that of other patients who were CYP3A5*3/*3 nonproducers (P<0.05), as well as 3435TT and 1236TT patients in the dose-adjusted Co. The patients of MDR1 SNPs, who were CYP3A4*18B or CYP3A5*1 producers, on CsA Co and dose-adjusted Co were lower than those with nonproducers.ConclusionPatients with variant genotypes have a higher Co than those with genotype wildtype genotype and heterozygote genotype in MDR1 SNPs. SNPs in MDR1 have influence on the cyclosporine pharmacokinetics and be responsible, in part, of the large interindividual variability of cyclosporine bioavailability. Patients who were CYP3A4 or CYP3A5 producers (with CYP3A4*18B or CYP3A5*1 allele) have a low cyclosporine concentration compared with nonproducers. CYP3A4 or CYP3A5 producers were partly responsible of cyclosporine bioavailability and contributed for one of the vital factories of interindividual variability of cyclosporine pharmacokinetics.