Association of CYP3A polymorphisms with the pharmacokinetics of cyclosporine A in early post-renal transplant recipients in China

Abstract

Aim: To evaluate retrospectively the association of cytochrome P450 3A (CYP3A) and ATP-binding cassette sub-family B member 1 (ABCB1) gene polymorphisms with the pharmacokinetics of cyclosporine A (CsA) in Chinese renal transplant patients. Methods: One hundred and twenty-six renal transplant patients were recruited. Blood samples were collected, and corresponding clinical indices were recorded on the seventh day after the procedure. The patients were genotyped for CYP3A4*1G, CYP3A5*3C, ABCB1 1236 C>T, ABCB1 2677 G>T/A, and ABCB1 3435 C>T polymorphisms. Whole blood trough concentrations of CsA at time zero (C 0 ) were measured before the drug administration. A multiple regression model was developed to analyze the effects of genetic factors on the CsA dose-adjusted C 0 (C 0 /dose) based on several clinical indices. Results: The CYP3A5*3C polymorphism influenced the C 0 and C 0 /dose of CsA, which were significantly higher in patients with the GG genotype than in patients with the AA or GA genotypes. No significant differences were detected for other SNPs (CYP3A4*1G, ABCB1 1236 C>T, ABCB1 2677 G>T/A, and ABCB1 3435 C>T). In a univariate analysis using Pearson's correlation test, age, hemoglobin, blood urea nitrogen and blood creatinine levels were significantly correlated with the log-transformed CsA C 0 /dose. In the multiple regression model, CYP3A5*3C, age, hemoglobin and blood creatinine level were associated with the log-transformed CsA C 0 /dose. Conclusion: CYP3A5*3C correlates with the C 0 /dose of CsA on the seventh day after renal transplantation. The allele is a putative indicator for the optimal CsA dosage in the early phase of renal transplantation in the Chinese population.

Associations of ABCB1, NFKB1, CYP3A, and NR1I2 polymorphisms with cyclosporine trough concentrations in Chinese renal transplant recipients

“…A series of studies examined the relationship between the CYP3A4*1G polymorphism and drug metabolism but resulted in inconsistent findings [32][33][34] . In agreement with our observation, CYP3A4*1G was not associated with cyclosporine concentrations in 126 renal recipients [27] ; however, Qiu et al [22] and Hu et al [35] found that it was associated with a lower CsA concentration. Differences in study populations, sample size, ethnicities and particularly in the duration after transplantation might be possible confounding factors.…”

“…Although the importance of CYP3A5*3 in tacrolimus concentrations has been fairly obvious, its influence on CsA concentrations is still in dispute. Several researchers [26][27][28] have observed a significant association between CYP3A5*3 and CsA trough concentrations. However, no association between CYP3A5*3 and CsA concentrations was found in this study, which is in consistent with some previous reports [29][30][31] .…”

Pharmacogenomics and personalized medicine: a review focused on their application in the Chinese population

“…Moreover, several studies of the CYP3A4*1G allele in intron 10 revealed that the CYP3A4*1G genotype had lower cyclosporine A clearance than CYP3A4*1/*1 in Han Chinese of East China [45] . To date, an association between CYP3A4*1G and www.chinaphar.com Shu WY et al Acta Pharmacologica Sinica npg cyclosporine A pharmacokinetics has not been established in patients after transplantation [42,46,47] . Interestingly, two separate studies conducted by two hospitals located in different regions of China presented conflicting results, although both included Han Chinese [45,46] .…”

“…The other study [45] was conducted in South China (Shanghai), where the majority of the population is Han Chinese. These conflicting results might be attributable to linkage disequilibrium (LD) between CYP3A4*1G and CYP3A5*3 in Asian populations [47][48][49] , including Han Chinese in South China [47] .…”

The Effect of ABCB1 C3435T Polymorphism on Cyclosporine Dose Requirements in Kidney Transplant Recipients: A Meta‐Analysis

“…Moreover, Meng et al . failed to find correlations between C3435T SNP and C 0 / D on the 7th day after transplantation. The reasons for these conflicting results remain unclear.…”