Relative impact of genotype and enzyme induction on the metabolic capacity of CYP2C9 in healthy volunteers.
Pharmacokinetics in individual subjects is determined by genes and environment. The relative contributions of enzyme induction and inherited genomic variation to cytochrome P450 enzyme 2C9 (CYP2C9) activity are unknown. In 130 volunteers, CYP2C9 activity was measured in vivo using tolbutamide as a probe drug. Tolbutamide was administered orally, and the pharmacokinetics of the drug was analyzed twice--before and after four doses of 450 mg rifampin. Mean total apparent clearances (Cl/F) in the genotype groups CYP2C9*1/*1, *1/*2, *1/*3, *2/*3, and *3/*3 before rifampin were 0.78, 0.74, 0.52, 0.40, and 0.13 l/h, respectively. After rifampin administration, these clearances increased in all genotype groups by a median factor of 1.9 (range 1.1-4.8). The combined effects of genes and environment could be predicted by a simple additive model. Thus, enzyme induction resulted in an approximately twofold difference in CYP2C9 activity, irrespective of the CYP2C9 genotypes. But the difference in activity levels between the CYP2C9*1/*1 and *3/*3 genotypes before the administration of rifampin was sixfold.
Department of Clinical Pharmacology, University Medical Center of the Georg August University Göttingen, Göttingen, Germany.
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SV
Vormfelde
J
J
Brockmöller
S
S
Bauer
P
P
Herchenhein
J
J
Kuon
I
I
Meineke
I
I
Roots
J
J
Kirchheiner
D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D004790:Enzyme Induction / Q000187:drug effects / Q000235:genetics; D005260:Female; D014644:Genetic Variation / Q000502:physiology; D005838:Genotype; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000235:genetics; D008875:Middle Aged; D014044:Tolbutamide / Q000494:pharmacology; D055815:Young Adult
D015415:Biomarkers; D014044:Tolbutamide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases