Measurement and compartmental modeling of the effect of CYP3A5 gene variation on systemic and intrarenal tacrolimus disposition.
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.
Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
S
S
Zheng
Y
Y
Tasnif
M F
MF
Hebert
C L
CL
Davis
Y
Y
Shitara
J C
JC
Calamia
Y S
YS
Lin
D D
DD
Shen
K E
KE
Thummel
D000328:Adult; D000465:Algorithms; D019540:Area Under Curve; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006207:Half-Life; D006579:Heterozygote; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000652:urine; D007668:Kidney / Q000378:metabolism; D008297:Male; D008957:Models, Genetic; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000652:urine
D007166:Immunosuppressive Agents; D004247:DNA; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus