RT Journal Article
SR Electronic
T1 EFFECT OF <em>CYP3A5</em> POLYMORPHISM ON TACROLIMUS METABOLIC CLEARANCE IN VITRO
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 836
OP 847
DO 10.1124/dmd.105.008680
VO 34
IS 5
A1 Dai, Yang
A1 Hebert, Mary F.
A1 Isoherranen, Nina
A1 Davis, Connie L.
A1 Marsh, Christopher
A1 Shen, Danny D.
A1 Thummel, Kenneth E.
YR 2006
UL http://dmd.aspetjournals.org/content/34/5/836.abstract
AB 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, Vmax was 8.0 and 17.0 nmol/min/nmol enzyme and Km,u was 0.21 and 0.21 μM, 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. The American Society for Pharmacology and Experimental Therapeutics