title: Impact of CYP2C9 and CYP2C19 polymorphisms on tolbutamide kinetics and the insulin and glucose response in healthy volunteers.
abstract: Tolbutamide is known to be metabolized by cytochrome P450 2C9 (CYP2C9), and the effects of the CYP2C9 amino acid polymorphisms *2 (Arg144Cys) and *3 (Ile359Leu) could be important for drug treatment with tolbutamide and for use of tolbutamide as a CYP2C9 test drug. Tolbutamide pharmacokinetics and plasma insulin and glucose concentrations were studied in 23 healthy volunteers with all six combinations of the CYP2C9 alleles *1, *2 and *3, including two subjects with the combined CYP2C9*1/*1 and CYP2C19*2/*2 genotype. Volunteers received a single oral dose of 500 mg tolbutamide, followed by 75 g oral glucose at 1, 4.5 and 8 h after tolbutamide administration. Pharmacokinetic analysis was performed using a computer program for regression analysis of nonlinear mixed effects models. The mean oral clearances of tolbutamide were 0.97 (95% confidence interval [CI] 0.89-1.05), 0.86 (95% CI 0.79-0.93), 0.75 (95% CI 0.69-0.81), 0.56 (95% CI 0.51-0.61), 0.45 (95% CI 0.41-0.49) and 0.15 (95% CI 0.14-0.16) l/h in carriers of CYP2C9 genotypes 1/*1, *1/*2, *2/*2, *1/*3, *2/*3 and *3/*3, respectively. Tolbutamide pharmacokinetics in carriers of the functionally deficient CYP2C19*2/*2 genotype were not different from those in the CYP2C19 highly active genotype. Elimination in the six CYP2C9 genotype groups could be expressed as the linear combination of three constants (0.05, 0.04, 0.01 h(-1), which were specific to the respective CYP2C9 alleles *1, *2 and *3, thus indicating a co-dominant mode of inheritance. Insulin and glucose concentration-time curves did not change with differing CYP2C9 genotypes. Tolbutamide was confirmed as a substrate of the genetically polymorphic enzyme CYP2C9. The pronounced differences in pharmacokinetics due to the amino acid variants did not significantly affect plasma insulin and glucose concentrations in healthy volunteers.
authors.affiliation: Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University, Berlin, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Kirchheiner
authors.forename: Steffen
authors.initials: S
authors.lastname: Bauer
authors.forename: Ingolf
authors.initials: I
authors.lastname: Meineke
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Rohde
authors.forename: Verena
authors.initials: V
authors.lastname: Prang
authors.forename: Christian
authors.initials: C
authors.lastname: Meisel
authors.forename: Ivor
authors.initials: I
authors.lastname: Roots
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brockmöller
mesh_terms: D000328:Adult; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases; D001786:Blood Glucose / Q000378:metabolism*; 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; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D007328:Insulin / Q000097:blood; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011159:Population Surveillance; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000235:genetics*; D013997:Time Factors; D014044:Tolbutamide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; 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; D007328:Insulin; 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