Artocarpin has shown anti-inflammation and anticancer activities. However, the metabolism differences among different species have not been reported. In this work, we used liver microsomes to explore the metabolic characteristics and possible metabolites of artocarpin among different species. The structures of six metabolites were characterized by LC-MS/MS, and hydroxylated artocarpin was the main metabolite. Enzyme kinetics and depletion studies of artocarpin among different species proved that artocarpin metabolism exhibited significant species differences; rats and monkeys showed a great metabolic ability to artocarpin, and minipigs showed the highest similarity to humans. The in vivo hepatic clearances of artocarpin in rats and humans were predicted that artocarpin was classified as a high-clearance drug in humans and rats. The glucuronidation assay of artocarpin in different liver microsomes also proved that artocarpin metabolism showed significant species difference. These findings will support further pharmacological or toxicological research on artocarpin.Abbreviations: UGT: UDP-glucuronosyltransferase; CYP: cytochrome P450; LC-MS/MS: liquid chromatography-tandem mass spectrometry; HPLC: high-performance liquid chromatography; HLMs: human liver microsomes; MLMs: monkey liver microsomes; RAMs: rabbit liver microsomes; RLMs: rat liver microsomes; DLMs: dog liver microsomes; PLMs: minipig liver microsomes; Vmax: maximum velocity; Km: Michaelis constant; CLint: intrinsic clearance; CLH: hepatic clearance; QH: hepatic blood flow.
Keywords: Artocarpin; LC-MS/MS; metabolism; species difference.