title: Tolbutamide, flurbiprofen, and losartan as probes of CYP2C9 activity in humans.
abstract: The metabolic activity of CYP2C9 in 16 subjects expressing four different genotypes (CYP2C9*1/*1, *1/*2, *1/*3, and *2/*2) was evaluated. Single oral doses of tolbutamide, flurbiprofen, and losartan were administered in a randomized, crossover design. Plasma and urine were collected over 24 hours. The urinary metabolic ratio and amount of metabolite(s) excreted were correlated with formation clearance. The formation clearance of tolbutamide to its CYP2C9-mediated metabolites demonstrated a stronger association with genotype compared to flurbiprofen and losartan, respectively (r2 = 0.64 vs. 0.53 vs. 0.42). A statistically significant correlation was observed between formation clearance of tolbutamide and the 0- to 12-hour urinary amount of 4'-hydroxytolbutamide and carboxytolbutamide (r = 0.84). Compared to tolbutamide, the correlations observed between the respective measures of flurbiprofen and losartan metabolism were not as strong. Tolbutamide is a better CYP2C9 probe than flurbiprofen and losartan, and the 0- to 12-hour amount of 4'-hydroxytolbutamide and carboxytolbutamide is the best urinary measure of its metabolism.
authors.affiliation: Divisions of Pharmacotherapy, CB# 7360, Beard Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Lee
authors.forename: John A
authors.initials: JA
authors.lastname: Pieper
authors.forename: Reginald F
authors.initials: RF
authors.lastname: Frye
authors.forename: Alan L
authors.initials: AL
authors.lastname: Hinderliter
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Blaisdell
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Goldstein
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005480:Flurbiprofen / Q000493:pharmacokinetics* / Q000652:urine; D005838:Genotype; D006801:Humans; D019808:Losartan / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D010641:Phenotype; D014044:Tolbutamide / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D005480:Flurbiprofen; D014044:Tolbutamide; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019808:Losartan