Inhibition of human liver microsomal CYP by nateglinide.

Objectives: Nateglinide is metabolized by CYP2C9 and CYP3A4, therefore drug-drug interactions through cytochrome P450 (CYP) inhibition may occur. In this study, we examined the inhibitory effects of nateglinide and its major metabolite N-[trans-4-(1-hydroxy-1-methylethyl)-cyclohexanecarbonyl]-D-phenylalanine (M1) on various CYP isoforms in human liver microsomes.

Methods: We used typical substrates (7-ethoxyresorufin for CYP1A1/2, tolbutamide for CYP2C9, S-mephenytoin for CYP2C19, bufuralol for CYP2D6, chlorzoxazone for CYP2E1 and midazolam for CYP3A4) in the evaluation of the inhibitory effects, and examined the possibility of mechanism-based inhibition (MBI) by evaluating the influence of pre-incubation in the inhibition.

Studies of the toxicological potential of capsinoids, XIII: inhibitory effects of capsaicin and capsinoids on cytochrome P450 3A4 in human liver microsomes.

This study evaluated potential effects of a number of capsinoids (ie, capsiate, dihydrocapsiate, nordihydrocapsiate) and a single capsaicinoid (ie, capsaicin) on liver microsomal cytochrome P450 3A4-mediated midazolam 1'-hydroxylase activity. Where possible, an inhibition curve was prepared; the concentration at which enzyme activity dropped to 50% was calculated. Capsaicin clearly inhibited cytochrome P450 3A4 activity, losing 50% of the activity at 21.

Studies of the toxicological potential of capsinoids, XII: pharmacokinetic study of capsinoid-containing CH-19 Sweet extract in rats.

Pharmacokinetics of the main capsinoid components of CH-19 Sweet extract (capsiate, dihydrocapsiate, and nordihydrocapsiate) were investigated in rats receiving a single gavage dose of extract containing 10 or 100 mg of capsinoids per kilogram in medium-chain triglyceride. Resultant blood levels of these capsinoids and a capsinoid metabolite, vanillyl alcohol, were measured in portal vein and systemic blood. Capsinoids were never detected.

Studies of the toxicological potential of capsinoids, XI: pharmacokinetic and tissue distribution study of 14C-dihydrocapsiate and metabolites in rats.

Pharmacokinetics of a single gavage dose of (14)C-labeled dihydrocapsiate (10 mg/kg) were investigated in male rats. Maximal plasma concentration was achieved in 40 minutes and exhibited an apparent half-life of 2.4 hours.

Studies of the toxicological potential of capsinoids: X. Safety assessment and pharmacokinetics of capsinoids in healthy male volunteers after a single oral ingestion of CH-19 Sweet extract.

The safety and pharmacokinetics of capsinoids, physiologically active ingredients of CH-19 Sweet extract, were investigated in 16 healthy male volunteers following a single oral ingestion of CH-19 Sweet extract. The study subjects consumed soft gel capsules containing either capsinoids (15 or 30 mg/person) or placebo. Capsinoids were well tolerated, and no clinically significant changes in physical examinations, blood pressure, heart rate, body temperature, electrocardiogram, hematology, blood chemistry, and urinalysis were observed at either the 15 or 30 mg dose.

Prediction of the metabolic interaction of nateglinide with other drugs based on in vitro studies.

Nateglinide is an antidiabetic agent metabolized by CYP2C9 and CYP3A4; hence inhibitors of these CYP isozymes may interact with nateglinide. There are, however, only limited in vitro data on how to predict drug-drug interactions in vivo. We examined the effects of 18 drugs that may be prescribed together with nateglinide (metformin, buformin, aspirin, gemfibrozil, simvastatin, pioglitazone, rosiglitazone, carbamazepine, clarithromycin, gliclazide, clofibrate, fluconazole, bezafibrate, phenylbutazone, nifedipine, famotidine, ibuprofen and miconazole) on the conversion of nateglinide to its major metabolite (N-[trans-4-(1-hydroxy-1-methylethyl)-cyclohexanecarbonyl]-D-phenylalanine) using human liver microsomes.