Untitled

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.

CYP2C9 Genotype vs. Metabolic Phenotype for Individual Drug Dosing—A Correlation Analysis Using Flurbiprofen as Probe Drug

“…However, they are mostly based on either in-vitro results, clinical studies with small healthy cohorts and/or heterogeneous cohorts of patients without consideration of concomitant medication, or meta analyses of these studies [4,16,17]. Only few data are available for cohorts where both typing procedures have been used on the same healthy persons, and there is a lack of statistical analysis of phenotypes to determine confidence limits for any estimated parameters [18]. Here, we provide this type of information for CYP2C9 activity by combining genotyping with phenotyping for a cohort of 283 healthy students, using FLB as probe drug.…”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…Celecoxib. CYP2C9*3 has been associated with reduced celecoxib metabolism in vitro and in five of six in vivo studies (Kirchheiner et al, 2003e;Tang et al, 2001;Werner et al, 2002;Stempak et al, 2005;Lundblad et al, 2006). Individuals heterozygous and homozygous for CYP2C9*3 had 1.5-and 3.0-fold higher AUCs in one single-dose study (Kirchheiner et al, 2003e).…”

“…CYP2C9*3 has been associated with reduced celecoxib metabolism in vitro and in five of six in vivo studies (Kirchheiner et al, 2003e;Tang et al, 2001;Werner et al, 2002;Stempak et al, 2005;Lundblad et al, 2006). Individuals heterozygous and homozygous for CYP2C9*3 had 1.5-and 3.0-fold higher AUCs in one single-dose study (Kirchheiner et al, 2003e). An earlier single-dose study reported that the three highest AUC values (ϳ2 times the mean AUC of all participants) were seen in carriers of *3 alleles (Tang et al, 2001), whereas another study reported that a PM had a 2-fold higher AUC than the mean of 11 EMs (genotyping was undertaken but only the predicted phenotype was reported) .…”

“…The conflicting steady-state results observed in the latter three studies are difficult to interpret but may relate to variable metabolism by alternate enzymes (e.g., CYP3A) in some individuals with CYP2C9 deficiency (Tang et al, 2001). CYP2C9*2 had no clinical PHARMACOGENETICS, DRUG METABOLISM, AND CLINICAL PRACTICE implications (Kirchheiner et al, 2003e;Tang et al, 2001;Sandberg et al, 2002;Brenner et al, 2003).…”

Pharmacokinetic and Pharmacodynamic Variability: A Daunting Challenge in Drug Therapy

“…Similarly, CYP2C9*3/*3 genotype has a greater impact on the kinetics of antidiabetic agents, such as glyburide and tolbutamide, compared to CYP2C9*2/*2 genotype [113,114]. The oral clearance value of glyburide was 54.3 ml/min in volunteers with CYP2C9*1/*1 genotype, 48.3 ml/min in those with CYP2C9*2/*2 genotype, and 11.2 ml/min in subjects with CYP2C9*3/*3 genotype.…”