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. Portal compartment vanillyl alcohol concentrations and area under the plasma concentration versus time curve increased approximately with dose, whereas the time to maximum concentration of vanillyl alcohol was independent of dose (30 minutes post dosing), suggesting that precipitation in the stomach or intestines was unlikely. Vanillyl alcohol levels were just barely detectable in systemic plasma (5 minutes post dosing). Significant levels of vanillyl alcohol conjugates, sulfate, and glucuronide were detected in the systemic blood. Given that the orally administered capsinoids were never detected in the portal vein or systemic circulation, these compounds must be broken down (chemically or enzymatically) to vanillyl alcohol.

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. Excretion of radioactivity in the urine, feces, and expired air was 78.2%, 19.4%, and 0.5% of the dose, respectively. Highest tissue concentrations were achieved in the kidney, liver, and blood; the data indicate that radioactivity accumulation following daily exposure at a dose of 10 mg/kg body weight is unlikely. Radioactivity in the plasma was associated with metabolites and their conjugates, probably vanillyl alcohol, vanillic acid, glucuronide of vanillyl alcohol, sulphate of vanillyl alcohol, and sulphate of vanillic acid. These results suggest dihydrocapsiate is metabolized by hydrolysis in the gut, or esterase or other enzymes in the blood, and the metabolites were rapidly absorbed and converted to their conjugates in the liver and eliminated by the kidneys into the urine.

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 21.5 micromol/L. No enzyme inhibition was observed in the presence of capsiate, dihydrocapsiate, or nordihydrocapsiate (<100 micromol/L). Preincubation increased the capsaicin inhibitory activity against cytochrome P450 3A4 in a time-dependent manner. Enzyme activity was slightly reduced by capsiate, dihydrocapsiate, and nordihydrocapsiate to the same level as that attained with tolbutamide, the negative control compound. Capsaicin was shown to inhibit cytochrome P450 3A4, probably through a mechanism-based inhibition. In contrast, capsiate, dihydrocapsiate, and nordihydrocapsiate did not inhibit cytochrome P450 3A4 activity and were unlikely to be mechanism-based inhibitors of CYP3A4.

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