title: Effects of CYP2C19 and CYP2C9 genetic polymorphisms on the disposition of and blood glucose lowering response to tolbutamide in humans.
abstract: Several recent in-vitro data have revealed that CYP2C19, in addition to CYP2C9, is also involved in the 4-methylhydroxylation of tolbutamide. We evaluated the relative contribution of CYP2C9 and CYP2C19 genetic polymorphisms on the disposition of blood glucose lowering response to tolbutamide in normal healthy Korean subjects in order to reappraise tolbutamide as a selective in-vivo probe substrate of CYP2C9 activity. A single oral dose of tolbutamide (500 mg) or placebo was administered to 18 subjects in a single-blind, randomized, crossover study with a 2-week washout period. Twelve subjects (of whom six were CYP2C19 extensive metabolizer (EM) and six were CYP2C19 poor metabolizer (PM) genotype) were of the homozygous wild-type CYP2C9*1 genotype; the other six subjects were of the CYP2C9*1/*3 and CYP2C19 EM genotype. Pharmacokinetic parameters were estimated from plasma and urine concentrations of tolbutamide and 4-hydroxytolbutamide. Serum glucose concentrations were measured before and after oral intake of 100 g dextrose. In subjects heterozygous for the CYP2C9*3 allele, C(max) and AUC of tolbutamide were significantly greater and the plasma half-life significantly longer than those in homozygous CYP2C9*1 subjects. No pharmacokinetic differences were found between CYP2C19 EM and PM genotype subjects. The estimated AUC of the increase in serum glucose after oral intake of 100 g dextrose was 2.7-fold higher in subjects with the wild-type CYP2C9 genotype than in those with CYP2C9*1/*3, but CYP2C19 genetic polymorphism did not alter the blood glucose lowering effect of tolbutamide. The plasma AUC of 4-hydroxytolbutamide and the ratio of 4-hydroxytolbutamide/tolbutamide did not differ significantly between CYP2C19 PM and EM genotype subjects, while these parameters were about twice as high in subjects with the wild-type CYP2C9 genotype than in heterozygous CYP2C9*3 subjects (P < 0.05). Our results strongly suggest that the disposition and hypoglycemic effect of tolbutamide are affected mainly by CYP2C9 genetic polymorphism, but not by CYP2C19 polymorphism. The in-vivo contribution of CYP2C19 to tolbutamide 4-methylhydroxylation appears to be minor in humans. This suggests that, at least in vivo, tolbutamide remains a selective probe for measuring CYP2C9 activity in humans.
authors.affiliation: Department of Pharmacology, Inje University College of Medicine and Clinical Pharmacology Center, Pusan Paik Hospital, Pusan, South Korea.
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Shon
authors.forename: Young-Ran
authors.initials: YR
authors.lastname: Yoon
authors.forename: Kyoung-Ah
authors.initials: KA
authors.lastname: Kim
authors.forename: Young-Chae
authors.initials: YC
authors.lastname: Lim
authors.forename: Kwang-Jae
authors.initials: KJ
authors.lastname: Lee
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Park
authors.forename: In-June
authors.initials: IJ
authors.lastname: Cha
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases; D001786:Blood Glucose / Q000378:metabolism*; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004341:Drug Evaluation; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006900:Hydroxylation; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D016037:Single-Blind Method; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics*; D014044:Tolbutamide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000652:urine; D000096926:Benzenesulfonamides
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D001786:Blood Glucose; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System; D007004:Hypoglycemic Agents; D006899:Mixed Function Oxygenases; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases; D014044:Tolbutamide; C031014:hydroxymethyltolbutamide; D000096926:Benzenesulfonamides; C450260:CYP2C9 protein, human; C045793:CYP2C19 protein, human