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.

No abstract

OATP1B1 and OATP1B3 may have contributed to the hepatic uptake of nateglinide, but the possibility of drug-drug interactions appeared to be low.

No abstract

Nateglinide and mitiglinide are immediate short-acting insulinotropic agents. Both are administered preprandially to control postprandial hyperglycemia. Glinide drugs are characterized by immediate onset as well as rapid disappearance of effect as compared with sulfonylurea drugs. We examined the rapidity of onset of the therapeutic effect between nateglinide and mitiglinide by pharmacokinetic/pharmacodynamic analysis using the receptor-binding-dissociation model in rats. Nateglinide or mitiglinide was administered orally or intravenously to rats and blood samples were collected at various time-points post administration. The plasma concentrations of the unbound drug forms and the blood glucose were measured. When the simultaneous fitting of oral administration and intravenous administration was performed using the receptor-binding-dissociation model, the measured values exhibited good correspondence with the fitting curve. Moreover, the time-courses of changes of the receptor-binding rate (sulfonylurea receptor) were examined using the parameters (k (on): second-order binding association constant to the receptor, Φ: receptor-binding occupancy ratio) obtained from the analysis. The results showed that the binding rate, which is important for glinide drugs in the early phase after administration, was obviously higher for nateglinide than that for mitiglinide from 10 min after oral administration and between 0 and 30 min after intravenous administration. These results suggest a more rapid onset of the therapeutic effect of nateglinide than that of mitiglinide after the drug is distributed into the blood.

The main metabolites were identified with authentic prothiofos and methyl esters of synthesized des-S-propyl prothiofos oxon (O-2,4-dichlorophenyl O-ethyl phosphate), despropyl prothiofos oxon (O-2,4-dichlorophenyl O-ethyl phospholothiolate), and des-S-propyl prothiofos (O-2,4-dichlorophenyl O-ethyl phosphorothioate). Despropyl prothiofos (O-2,4-dichlorophenyl O-ethyl phosphorodithioate) was also identified in plasma. Large amounts of the hydrolyzed product, 2,4-dichlorophenol and its conjugate were also found. The metabolic pattern of prothiofos in humans appears to be different from that in rats.