Measurement and Compartmental Modeling of the Effect of CYP3A5 Gene Variation on Systemic and Intrarenal Tacrolimus Disposition

Abstract

We evaluated the hypothesis that CYP3A5 expression can affect intrarenal tacrolimus accumulation. An oral dose of tacrolimus was administered to 24 healthy volunteers who were selected based on their CYP3A5 genotype. Compared to CYP3A5 nonexpressors, expressors had a 1.6-fold higher oral tacrolimus clearance and 2.0- to 2.7-fold higher metabolite/parent AUC ratios for 31-DMT, 12-HT and 13-DMT. In addition, the apparent urinary tacrolimus clearance was 36% lower in CYP3A5 expressors, compared to nonexpressors. To explore the mechanism behind this observation, we developed a semi-physiological model of renal tacrolimus disposition and predicted that tacrolimus exposure in the renal epithelium of CYP3A5 expressors is 53% of that for CYP3A5 nonexpressors, when normalized to blood AUC. These data suggest that at steady state, intrarenal accumulation of tacrolimus, and its primary metabolites, will depend on the CYP3A5 genotype of the liver and kidneys. This may contribute to inter-patient differences in the risk of tacrolimus-induced nephrotoxicity.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing

“…CYP3A5*1/*3 is believed to explain up to 45% of the variability in tacrolimus dose . Because of the rarity of the CYP3A5*6 and CYP3A5*7 alleles in most populations (see Supplementary Table S3 online), their impact on tacrolimus dose‐adjusted trough concentrations has only been examined in combined analyses with CYP3A5*3 . However, because both alleles result in a nonfunctional protein, their impact on tacrolimus clearance and dose‐adjusted trough concentrations is presumed to be identical to CYP3A5*3 .…”

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

“…[57][58][59][60] CYP3A5 is the only CYP3A isozyme expressed in the kidney and may limit local exposure to CNIs by intra-renal metabolism. [61,62] Zheng et al [63] demonstrated that Tac concentrations in the renal epithelium of CYP3A5 expressers are 53% lower compared with CYP3A5 non-expressers.…”

Genetic variance in ABCB1 and CYP3A5 does not contribute toward the development of chronic kidney disease after liver transplantation

“…Until recently, because of analytical difficulties, it was not possible to measure intrarenal Tac concentrations [41]. However, the influence of ABCB1 3435C > T on the pharmacokinetics of Tac is questionable and probably limited [42][43][44]. A recent study by Zheng and colleagues provided some evidence that the CYP3A5 genotype may be a determinant for intrarenal Tac concentrations [42].…”