| Summary: | 碩士 === 國立成功大學 === 臨床藥學研究所 === 97 === Introduction. Natural phenolic compound is abundant in daily foods. Studies in recent years have reported that this class of compounds contains numerous beneficial health effects. Sesamol is one of the phenolic compounds in sesame. It was produced from sesamolin during the bleaching process of sesame oil with acid clay or upon roasting of sesame seed. Several effects of sesamol, including free radical scavenging, antioxidation, preventing cardiovascular diseases, and chemoprevention have been reported by previous in vitro studies.
Sesamol undergoes rapid and extensive phase II conjugation metabolism and converts to sesamol glucuronide and sesamol sulfate. Glucuronidation is mediated by uridine diphosphateglucuronosyl transferases (UGTs) and is a common metabolic pathway for various drugs. Therefore, it is of great importance to examine the pharmacokinetic interactions between sesamol and drugs that are UGTs substrates.
Purpose. The aim of this study was to investigate the pharmacokinetics and drug interactions of sesamol in SD rats. A sensitive HPLC method for simultaneous determination of sesamol and its conjugate metabolites in rat plasma was also developed for the purpose.
Method. Rats received several dose levels of sesamol intravenously and orally in the control groups. In the experiment groups, rats received sesamol after the treatment with valproic acid. Concentrations of sesamol, its metabolites and valproic acid were followed at scheduled intervals after drug administration to characterize their kinetic profiles in rats.
Result. A sensitive HPLC method for the analysis of sesamol and its major metabolites in biological fluid was developed. The method was applied successfully to pharmacokinetic studies of sesamol in rats. Following bolus injection of 5-30 mg/kg to rats, the disposition of sesamol in plasma was linear. However, nonlinear disposition was evident after oral administration of 15-50 mg/kg of sesamol with the bioavailability of 10.3-35.2%. After co-administration with valproic acid intravenously, the plasma levels of valproic acid，sesamol and its conjugate metabolites were rapidly decreased. In the oral experiment group, the plasma levels of valproic acid and sesamol were increased and the major metabolites of sesamol were decreased one hour later.
Conclusion. Sesamol undergoes rapid and extensive conjugation metabolism and converts to sesamol glucuronide and sesamol sulfate. Saturation of sulfation might be an explanation for the nonlinear pharmacokinetics of sesamol in the oral control groups. Co-administration of the UGTs substrates sesamol and valproic acid by oral route in rats resulted in a two-fold increase of the maximum concentration of valproic acid with plasma level higher than the therapeutic range. These drug interactions may produce adverse reactions, and even the toxic effects. In the bolus injection group, the interactions caused the rapid decrease of plasma valproic acid concentration to sub-therapeutic levels and may resulte in the development of epileptic seizures.
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