EFFECT OFCYP3A5POLYMORPHISM ON TACROLIMUS METABOLIC CLEARANCE IN VITRO

Abstract

ABSTRACT:Previous investigations of solid organ transplant patients treated with tacrolimus showed that individuals carrying a CYP3A5*1 allele have lower dose-adjusted trough blood concentrations compared with homozygous CYP3A5*3 individuals. The objective of this investigation was to quantify the contribution of CYP3A5 to the hepatic and renal metabolic clearance of tacrolimus. Four primary tacrolimus metabolites, 13-O-desmethyl tacrolimus (13-DMT) (major), 15-O-desmethyl tacrolimus, 31-O-desmethyl tacrolimus (31-DMT), and 12-hydroxy tacrolimus (12-HT), were generated by human liver microsomes and heterologously expressed CYP3A4 and CYP3A5. The unbound tacrolimus concentration was low (4-15%) under all incubation conditions. For CYP3A4 and CYP3A5, V max was 8.0 and 17.0 nmol/min/nmol enzyme and K m,u was 0.21 and 0.21 M, respectively. The intrinsic clearance of CYP3A5 was twice that of CYP3A4. The formation rates of 13-DMT, 31-DMT, and 12-HT were >1.7-fold higher, on average, in human liver microsomes with a CYP3A5*1/*3 genotype compared with those with a homozygous CYP3A5*3/*3 genotype. Tacrolimus disappearance clearances were 15.9 ؎ 9.8 ml/min/mg protein and 6.1 ؎ 3.6 ml/ min/mg protein, respectively, for the two genotypes. In vitro to in vivo scaling using both liver microsomes and recombinant enzymes yielded higher predicted in vivo tacrolimus clearances for patients with a CYP3A5*1/*3 genotype compared with those with a CYP3A5*3/*3 genotype. In addition, formation of 13-DMT was 13.5-fold higher in human kidney microsomes with a CYP3A5*1/*3 genotype compared with those with a CYP3A5*3/*3 genotype. These data suggest that CYP3A5 contributes significantly to the metabolic clearance of tacrolimus in the liver and kidney.

Calcineurin Inhibitor Nephrotoxicity

“…Because this association was found with recipient's CYP3A5 genotype (which will affect intestinal and hepatic but not renal allograft CYP3A5), hepatic and intestinal CYP3A5 should be responsible for this and would affect the levels of tacrolimus metabolites in the blood. Indeed, the generation of tacrolimus metabolites was higher in liver microsomes expressing CYP3A5 compared with nonexpressing microsomes, and kidneys contribute only marginally to tacrolimus metabolism (310). The CYP3A5 genotype of the kidney donors was not assessed in this study (234).…”

Pharmacogenetics of Immunosuppressive Drugs in Renal Transplantation

“…The intrinsic clearance of cyclosporine, calculated from total metabolite formation, is approximately 2.3-fold higher for CYP3A4 than for CYP3A5 (Dai et al, 2006). Still, the results of studies conducted so far do not indicate a clear relationship (Anglicheau et al, 2007) with 3A4 isoform.…”

“…This plasmatic clearance is higher in those individuals with genotype CYP3A5*1/*3 regarding those CYP3A5*3/*3 (Haufroid et al, 2006). In fact, CYP3A5*1 is responsible from about 60% of tacrolimus hepatic metabolism (Dai et al, 2006;Thervet et al, 2010), so it is of great interest studying it in order to establish optimal doses that reach quickly the efficient blood concentrations, avoiding toxicity but also assuring the necessary concentrations to avoid rejection. The studies performed so far indicate the need to administrate higher tacrolimus doses in patients CYP3A5*1/*1.…”

Pharmacogenomic associations in ABCB1 and CYP3A5 with acute kidney injury and chronic kidney disease after myeloablative hematopoietic cell transplantation

“…CNI exposure in the kidney tubular cells is primarily mediated by the drugmetabolizing enzyme cytochrome P450 3A5 (CYP3A5) and the drug transporter P-glycoprotein (P-gp), which is encoded by the mutidrug resistance gene (ABCB1, also known as MDR1). [5][6][7] Genetic variability in the CYP3A5 and ABCB1 genes may alter the metabolism and transport of CNIs in renal tubular cells and may be an important risk factor for AKI and CKD post-HCT. 8,9 Our goal was to evaluate the pharmacogenomic associations between the CYP3A5 and ABCB1 genotypes and the risk of CNI-induced renal injury in a retrospective study in our cohort of HCT patients.…”