OBJECTIVE To investigate pharmacokinetic and pharmacodynamic factors associated with population differences in warfarin doses needed to achieve anticoagulation, in particular the possible involvement of genetic variability in vitamin K epoxide reductase (VKOR) and CYP2C9. METHODS Warfarin maintenance dose, unbound plasma S-warfarin concentration [Cu(S)] and INR were determined in 157 Caucasia...

Human cytochrome P450 (CYP) is a superfamily of hemoproteins which oxidize a number of endogenous compounds and xenobiotics. The human CYP2C subfamily consists of four members: CYP2C8, CYP2C9, CYP2C18 and CYP2C19. CYP2C9 and CYP2C19 are important drug-metabolizing enzymes and together metabolize approximately 20% of therapeutically used drugs. Forty-two allelic variants for CYP2C9 and 34 for CY...

The inhibitory effect of glyburide [International Nonproprietary Name (INN), glibenclamide] on CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 activities was evaluated using pooled human liver microsomes. Glyburide strongly inhibited CYP2C9-catalyzed S-warfarin and phenytoin metabolism in a competitive manner, with Ki (IC50) values of 2.4 (11.3) microM and 3.1 (9.4) microM, respecti...

Cytochrome P450 2C9 (CYP2C9) metabolizes dehydroepiandrosterone-sulfate (DHEA-S), but in elderly people the amount of DHEA-S remaining after CYP2C9 metabolization may be insufficient for optimal health. A prediction model, molecular docking, and molecular dynamics were used to screen the Traditional Chinese Medicine (TCM) database to determine molecular compounds that may inhibit CYP2C9. The ca...

BACKGROUND Vitiligo is a depigmenting skin disorder in which genetic factors play an important role. OBJECTIVE To examine the association of CYP2C9 (*) 1/(*) 2/(*) 3 gene polymorphism with vitiligo. METHODS In this case controlled study, 95 Saudi patients with vitiligo (50 men and 45 women), with a mean age of 27.3 years, were analyzed. Patients were compared to 86 healthy controls from the...

A common feature of many CYP2C9 ligands is their weak acidity. As revealed by crystallography, the structural basis for this behavior involves a charge-pairing interaction between an anionic moiety on the substrate and an active site R108 residue. In the present study we attempted to re-engineer CYP2C9 to better accept basic ligands by charge reversal at this key residue. We expressed and purif...

The in vitro inhibitory effects of gemfibrozil on cytochrome P450 (CYP) 1A2 (phenacetin O-deethylation), CYP2A6 (coumarin 7-hydroxylation), CYP2C9 (tolbutamide hydroxylation), CYP2C19 (S-mephenytoin 4'-hydroxylation), CYP2D6 (dextromethorphan O-deethylation), CYP2E1 (chlorzoxazone 6-hydroxylation), and CYP3A4 (midazolam 1'-hydroxylation) activities were examined using pooled human liver microso...

Using selective cytochrome P450 (CYP) inhibitors and clinical concentrations (4 microM) of dapsone (DDS), we found a major contribution of CYP2C9 and little or no contribution (< or = 10%) of CYP3A4 and CYP2E1 to dapsone N-hydroxylation (DDS-NHY) in human liver microsomes. Sulfaphenazole (2.16 microM) and tolbutamide (500 microM), selective inhibitors of CYP2C9 (or 2C8/9), inhibited DDS-NHY by ...

Genetic variants in CYP2C9 and VKORC1 strongly affect steady-state warfarin dose. However, these variants also affect early international normalized ratio (INR) values during warfarin initiation. We examined whether CYP2C9/VKORC1 genotypes provide information about warfarin sensitivity additional to that provided by early INR responses. In 214 patients starting warfarin with INR-guided dose adj...

Current dosing algorithms do not account for genetic and environmental factors for warfarin dose determinations. This study investigated the contribution of age, CYP2C9 and VKORC1 genotype, and body size to warfarin-dose requirements. Studied were 297 patients with stable anticoagulation with a target international normalized ratio (INR) of 2.0 to 3.0. Genetic analyses for CYP2C9 (*2 and *3 all...