CYP3A7, CYP3A5, CYP3A4, and ABCB1 Genetic Polymorphisms, Cyclosporine Concentration, and Dose Requirement in Transplant Recipients

Abstract

Cyclosporine is a substrate of cytochrome P450 (CYP) 3A and of the transporter ABCB1, for which polymorphisms have been described. In particular, CYP3A5 *3/*3 genotype results in the absence of CYP3A5 activity, whereas CYP3A7 *1/*1C genotype results in high CYP3A7 expression in adults. Log-transformed dose-adjusted cyclosporine trough concentration and daily dose per weight were compared 1, 3, 6, and 12 months after transplantation between CYP3A and ABCB1 genotypes in 73 renal (n = 64) or lung (n = 9) transplant recipients. CYP3A5 expressors (*1/*3 genotype; n = 8-10) presented significantly lower dose-adjusted cyclosporine trough concentrations (P < 0.05) and required significantly higher daily doses per weight (P < 0.01) than the nonexpressors (*3/*3 genotype; n = 55-59) 1, 3, 6, and 12 months after transplantation. In addition, 7 days after transplantation, more CYP3A5 expressors had uncorrected trough cyclosporine concentration below the target concentration of 200 ng/mL than the nonexpressors (odds ratio = 7.2; 95% confidence interval = 1.4-37.3; P = 0.009). CYP3A4 rs4646437C>T influenced cyclosporine kinetics, the T carriers requiring higher cyclosporine dose. CYP3A7*1C carriers required a 1.4-fold to 1.6-fold higher cyclosporine daily dose during the first year after transplantation (P < 0.05). In conclusion, CYP3A4, CYP3A5, and CYP3A7 polymorphisms affect cyclosporine metabolism, and therefore, their genotyping could be useful, in association with therapeutic drug monitoring, to prospectively optimize cyclosporine prescription in transplant recipients. The administration of a CYP3A genotype-dependent cyclosporine starting dose should therefore be tested prospectively in a randomized controlled clinical trial to assess whether it leads to an improvement of the patients outcome after transplantation, with adequate immunosuppression and decreased toxicity.

Diltiazem augments the influence of MDR1 genotype status on cyclosporine concentration in Chinese patients with renal transplantation

“…Among the 50 SNPs of the MDR1 gene, the mutation at position 3435 in exon 26 is the only silent polymorphism identified to date that might influence P-gp expression in different human tissues and different ethnic groups [28] . Previous studies have reported similar results, showing that MDR1 C3435T did not influence the adjusted CsA trough blood concentration in patients who did not use diltiazem during the early and stable posttransplant periods [18,20,25] . We cannot explain this change in relationship; however, we speculate that this change might partially reflect the nature of diltiazem, which is a substrate and inhibitor of P-gp.…”

“…Consistent results were obtained in another study involving American renal transplant patients [19] . Crettol et al [20] also reported that MDR1 genotypes did not influence the dose-adjusted trough blood concentration of CsA in transplant recipients. In contrast, Chinese renal transplant patients showed that MDR1 G2677T/A and MDR1 haplotypes C-G-C, T-G-T and T-T-C are associated with the CsA concentration during the early post- Figure 3.…”

“…In recent years, high inter-individual heterogeneity in the MDR1 gene, influencing the metabolism of digoxin [15][16][17] , cyclosporin [18][19][20] , tacrolimus [21][22][23] and amlodipine [24] , has been described. In the present study, we explored the association of MDR1 SNPs with CsA dose requirements and adjusted concentration in renal recipients co-treated or not with diltiazem.…”

IL-3 and CTLA4 gene polymorphisms may influence the tacrolimus dose requirement in Chinese kidney transplant recipients

“…The results are consistent with the research results of Li et al [19] . A previous study suggested that the rs4646437-T allele was in strong LD (r 2 =0.82) with the CYP3A5*1 allele in Caucasian renal transplant recipients [40] . A study of Chinese groups showed a moderate degree (r 2 =0.502) of LD between rs2242480 and rs776746, and a low degree (r 2 =0.244) of LD between rs4646437 and rs776746 [19] .…”

Calcineurin Inhibitor-Induced Renal Allograft Nephrotoxicity

“…Other studies however failed to confirm this association 82,83 obviously by reason of low population frequency of CYP3A4*1B allele and difficulties in acquiring adequate numbers of subjects for valid statistical analysis. In carriers of at least one wild-type CYP3A5*1 allele, cyclosporine administration was associated with significantly lower AUCs compared to CYP3A5*3 homozygotes with low CYP3A5 enzyme activity, where adequate levels of cyclosporine could be achieved with lower doses [84][85][86][87] . However these finding have not been confirmed by other authors again [88][89][90] .…”