The effect of CYP3A4, CYP3A5 and MDR1 (ABCB1) single nucleotide polymorphisms on the pharmacokinetics of cyclosporine in Algerian stable renal transplant recipients.

Abstract

Background: Cyclosporine (CsA) is a calcineurin inhibitor (CNI) commonly prescribed after organ transplantation to reduce the risk of graft rejection and prolong both graft and patient survival. However, its clinical use is often limited by a narrow therapeutic index and highly variable, unpredictable pharmacokinetics. Consequently, close therapeutic monitoring is essential to ensure effective immunosuppression. Genetic polymorphisms in cytochrome P450 3 A (CYP3A) enzymes and the multidrug resistance gene 1 (ABCB1) may influence CsA dose requirements and blood concentrations in renal transplant recipients.

Methods and results: This study aimed to evaluate the impact of selected single nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, and ABCB1 genes in a cohort of Algerian renal transplant patients. Fifty stable kidney transplant recipients were enrolled. SNPs of CYP3A4, CYP3A5 and ABCB1 genes were detected with direct sequencing and associations between genotypes and CsA dose requirements, trough concentrations (C₀), 2 h post dose concentration (C₂) and dose-adjusted trough levels (C/D) were investigated. A significant decrease of CsA trough concentration C₀ and C₀/D ratio was observed in the carriers of the heterozygote genotype CYP3A5*1/3 against homozygote ones CYP3A53/*3 (43.86 ± 16.53 vs. 58.21 ± 24.31 ng/mL per mg per kg); p = 0.039. Moreover, the CYP3A5 *1/3 genotype was associated with significantly lower cholesterol levels compared to patients carrying the CYP3A53/*3 genotype (14.20 ± 10.66 vs. 33.11 ± 20.69); p = 0.0002. In contrast, the ABCB1 3435 C > T polymorphism (C/C, C/T, or T/T genotypes) showed no significant association with CsA pharmacokinetics.

Conclusions: In conclusion, the CYP3A5 A6986G (*3/*3) polymorphism is significantly associated with higher CsA trough levels and dose-adjusted concentrations, as well as increased cholesterol levels in stable renal transplant recipients even with similar doses. Conversely, variability in CsA pharmacokinetics does not appear to be significantly influenced by ABCB1 3435 C > T polymorphisms.