Influence of MDR1 and NFKBIA polymorphisms on Cyclosporin A concentrations in Chinese renal transplant recipients

Cyclosporine (CsA) is the first-line immunosuppressants widely used to prevent allograft rejection after renal transplantation. But it has a narrow therapeutic index and shows considerable inter-individual differences in its pharmacokinetics. At the same time, Cyclosporine is a substrate of CYP3A4 and P-glycoprotein (P-gp, encoded by MDR1 gene). Nuclear factor kappa-B (NFκB) plays a crucial role in suppression of CYP3A4 expression^[1], and NFκB inhibitor α (IκBα, encoded by NFKBIA gene) has been reported to downregulate the activity of  NFκB. Thus, inter-individual differences in the activity and/or expression of CYP3A4, P-gp^[2] and NFκB may contribute considerably to cyclosporine A pharmacokinetics.

Objective: To investigate the association of MDR1 and NFKBIA polymorphisms with cyclosporine concentrations in Chinese renal transplant recipients.

Method: A total of 88 renal transplant recipients receiving cyclosporine were genotyped by polymerase chain reaction–restriction fragment length polymorphism for MDR1 G2677T/A, C3435T, and NFKBIA G2758A. Cyclosporine whole blood levels were measured by fluorescence polarization immunoassay.Trough concentration (C₀) of cyclosporine during days 6-18 after transplantation was determined.

Results: Dose-adjusted C₀ of cyclosporine in MDR1 2677TT carriers was significant higher than those in GG plus GT carriers (90.38±24.46 vs. 66.89±25.66 ng/mL per mg/kg, P<0.001). MDR1 3435TT carriers had significant higher dose-adjusted C₀ of cyclosporine than those in CC plus CT carriers (91.96±24.01 vs. 68.95±26.82 ng/mL per mg/kg, P=0.002). When combined the effects of MDR1 G2677T/A and C3435T, the carriers of haplotype T-T had an obviously higher dose-adjusted C₀ of cyclosporine than carriers of other haplotypes (97.23±21.78 vs. 68.38±26.36 ng/mL per mg/kg, P<0.0001). In addition, dose-adjusted C₀ of cyclosporine in NFKBIA 2758AA carriers were significant higher than those in GA plus GG carriers (81.93±27.37 vs. 59.77±22.97 ng/mL per mg/kg, P<0.0001). In this analysis, MDR1 G2677T/A and NFKBIA G2758A contributed most to the inter-individual variability in cyclosporine trough concentration, accounting for 24.6% and 14.6%, respectively.

Conclusion: These results indicated that MDR1 2677TT, 3435TT and NFKBIA 2758AA genotype were closely correlated with cyclosporine trough concentrations. It suggested that these SNPs may play a key role in optimal dosing regimen of cyclosporine.

 

References

 [1] Gu, X. "Role of NF-κB in Regulation of PXR-mediated Gene Expression: a mechanism for the suppression of cytochrome P-450 3A4 by proinflammatory agents. Journal of Biological Chemistry. 2006. 281(26): 17882-17889.

 [2] Wang, Y., C. Wang, et al. Effect of genetic polymorphisms of CYP3A5 and MDR1 on cyclosporine concentration during the early stage after renal transplantation in Chinese patients co-treated with diltiazem. European Journal of Clinical Pharmacology. 2008.65(3): 239-247.