CYP3A5 and CYP3A4 but not MDR1 Single-nucleotide Polymorphisms Determine Long-term Tacrolimus Disposition and Drug-related Nephrotoxicity in Renal Recipients

Abstract

The impact of CYP3A and MDR1 gene single-nucleotide polymorphisms on long-term tacrolimus disposition and drug-related toxicity has not been assessed. A study was performed in 95 genotyped recipients by measuring (12 and 4 h) concentration-time curves on day 7; 3, 6 months; 1, 2, 3, 4, and 5 years after transplantation. In contrast to recipients carrying the CYP3A4*1/CYP3A5*1 or CYP3A4*1B/CYP3A5*1 genotypes, dose-corrected tacrolimus exposure almost doubled over 5 years in patients with the CYP3A4*1/ CYP3A5*3 genotype (AUC(0-12 h): from 41.7+/-18.7 to 80+/-39.2 ng h/ml/mg; P<0.05), whereas apparent oral steady-state clearance and dose requirements significantly decreased accordingly. The CYP3A4*1/CYP3A5*1 and CYP3A4*1B/CYP3A5*1 genotypes were significantly more frequently associated with the development of biopsy-proven tacrolimus-related nephrotoxicity than the CYP3A4*1/ CYP3A5*3 genotype (37.5 vs 11.2%; P=0.03 and 42.8 vs 11.2%; P=0.02). The lack of a time-related increase in dose-corrected tacrolimus exposure observed with the CYP3A4*1/CYP3A5*1 and CYP3A4*1B/CYP3A5*1 genotypes is associated with tacrolimus-related nephrotoxicity, possibly as a result of higher concentrations of toxic metabolites.

Pharmacogenetics and Renal Transplantation

“…This difference remained significant at 1 month and 3 months post-transplant (Zhang et al, 2005). A temporal change in Tac oral bioavailability has been reported by Kuypers et al The dosenormalized exposure to Tac increased progressively over a 5-year period in individuals predicted to be CYP3A5 non-expressers but not in CYP3A5 expressers (Kuypers et al, 2007). The frequency of these alleles depends on the population studies: the CYP3A5*1 allele is present in 15 % of the Caucasian, 45% of the African-American (Kuehl et al, 2001), and 25% of the Chinese population (Balram et al, 2003).…”

Emerging Role of Pharmacogenetic in Organ Transplantation

“…In fact, in this multi-center randomized controlled trial, patients receiving tacrolimus daily dose according to their CYP3A5 genotype, achieved the target concentration more rapidly with lesser dose modification and in an higher percentage ( >75%) when compared to those in whom tacrolimus was managed with a concentrationcontrol strategy [21]. ABCB1 polymorphisms do not seem to influence tacrolimus pharmacokinetic and research into this association has yielded mixed results [22,23]. Nevertheless, in our series we observed a significant reduction in tacrolimus concentration and dose-adjusted tacrolimus concentrations in the early post-transplant period for the TT polymorphism of C1236T; this suggests that there is higher metabolism of the drug in subjects with this genotype [24].…”

Calcineurin Inhibitor-Induced Renal Allograft Nephrotoxicity

“…However, the effects of these metabolites on tubular function, expression of TGF-β, and other aspects of CI nephrotoxicity are currently unknown. The nephrotoxic potential of tacrolimus metabolites has not been studied yet, however suspicion for their toxicity is supported by the fact that recipients of kidneys who express CYP3A5 (carriers of polymorphism CYP3A5*1) have higher risk of development of chronic CI nephrotoxicity compared to non-expressors (CYP3A5*3/*3) 111,112 . Our knowledge is insufficient for a final verdict as to whether cyclosporine and tacrolimus metabolites contribute to development of nephrotoxicity.…”