Measurement and compartmental modeling of the effect of CYP3A5 gene variation on systemic and intrarenal tacrolimus disposition

Abstract

We evaluated the hypothesis that cytochrome P450 3A5 (CYP3A5) expression can affect intrarenal tacrolimus accumulation. Tacrolimus was administered orally to 24 healthy volunteers who were selected on the basis of their CYP3A5 genotype. As compared with CYP3A5 nonexpressors, expressors had a 1.6-fold higher oral tacrolimus clearance and 2.0- to 2.7-fold higher metabolite/parent area under the curve (AUC) ratios for 31-desmethyl tacrolimus (31-DMT), 12-hydroxy tacrolimus, and 13-desmethyl tacrolimus (13-DMT). In addition, the apparent urinary tacrolimus clearance was 36% lower in CYP3A5 expressors as compared with nonexpressors. To explore the mechanism behind this observation, we developed a semiphysiological 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 interpatient differences in the risk of tacrolimus-induced nephrotoxicity.

Figure 1

Mean log concentration–time profiles of tacrolimus and its four primary metabolites after oral tacrolimus administration in (A) CYP3A5 expressors (n = 12) and (B) CYP3A5 nonexpressors (n = 12). Also shown are AUC_metabolite to AUC_parent ratios for the four primary metabolites of tacrolimus (C): AUC_12-HT /AUCp, AUC_31-DMT/AUCp, AUC_13-DMT/AUCp and AUC_15-DMT/AUCp. The solid line represents the mean ratios; *** P < 0.0001.

Figure 2

Serial calculations of the apparent urinary tacrolimus clearance based on blood concentrations; * P < 0.05; ** P < 0.005.

Figure 3

Compartmental model scheme for renal disposition. Rate constant, compartment labels and parameters are defined in the figure.

Figure 4

Model fit to the mean tacrolimus urine excretion data in CYP3A5 expressors and nonexpressors, simultaneously, using blood concentration as a forcing function.

Figure 5

The simulated tacrolimus exposure in the renal epithelium. (A) Simulated tacrolimus amount in the renal epithelium (logarithmic amount shown in the upper insert) and (B) Area under the simulated amount_{renal epithelium} - time curve normalized to blood AUC_(0–96h); *** P < 0.0001.