Characterization of in vitro metabolites of rutaecarpine in rat liver microsomes using liquid chromatography/tandem mass spectrometry

Abstract

Following incubation of rutaecarpine, a new cyclooxygenase-2 inhibitor, with rat liver microsomes, the structures of the metabolites were characterized by liquid chromatography with tandem mass spectrometry. Nine metabolites corresponding to mono- or dihydroxylated rutaecarpine were formed. Characteristic product ions for the identification of rutaecarpine metabolites were observed at m/z 136, 158 and 286. The loss of water led to the fragment ion at m/z 286, indicating the hydroxylation of the aliphatic ring. The fragment ion at m/z 136 indicated the hydroxylated form of the phenyl group of the quinazolinone moiety, while that at m/z 158 indicated the hydroxylated form of the aromatic ring of the indole moiety.

Effect of Phenobarbital on the Pharmacokinetics of Rutaecarpine and its Metabolite in Rats

“…These results clearly indicated that the induction of CYP by PB significantly increased in the metabolism of rutaecarpine to its phase I metabolite. The present results were consistent with our previous reports that the metabolism of rutaecarpine is CYP dependent in rat liver microsomes (Lee et al, 2004a, Lee et al, 2004b. Although only one metabolite was detected in the present study, it was evident that PB can modulate the metabolism of rutaecarpine in rats.…”

“…As mentioned in the Introduction, rutaecarpine has beneficial pharmacological activities including anti-inflammatory activities (Moon et al, 1999, Woo et al, 2001). In addition, we have recently identified 9 phase I metabolites with their chemical structures by using tandem mass spectrometry (Lee et al, 2004b). Therefore, rutaecarpine would be a good model compound to study the drug-drug interaction, because one can study the possible kinetic changes in metabolite production together with the parent drug.…”

“…More recently, in order to develop rutaecarpine as an anti-inflammatory agent, a simple and practical method for the synthesis of rutaecarpine in a large quantity was successfully established by our group . Previous studies reported that cytochrome P450 (CYP) 1A and 2B might predominantly metabolize rutaecarpine in rat liver microsomes (Lee et al, 2004a) and that nine phase I metabolites of rutaecarpine were identified by using liquid chromatographyelectrospray ionization tandem mass spectrometry (Lee et al, 2004b).…”

Synthesis and Biological Properties of Benzo-Annulated Rutaecarpines

“…15) Such a variety of intriguing biological properties have led not only to the development of synthetic methods [16][17][18][19][20] but also to the systematic examination of its metabolites. [21][22][23] Although the action mechanisms of antiinflammatory, 3) vasorelaxing, 6) antiplatelet, 8) and antiobesity 11) effect of rutaecarpine have been studied, those of cytotoxicity have not been pursued as yet. Continuing interest in rutaecarpine 17,18,21,22,24,25) and in the effect of benzoannulation on chemical 26) and/or biological properties 27) spurred us to prepare a series of benzo-annulated rutaecarpines, especially on rings A and E, and to examine their biological properties focusing on the inhibitory activities in selected human cancer cell lines.…”

Effects of Rutaecarpine on the Pharmacokinetics of Caffeine and Its Three Metabolites in Rats

“…For this reason, many researchers enthusiastically work in the fi elds of the identifi cation of new constituents with biological activities, the total or semi-synthesis of active constituents, and characterization of their metabolic profi les in vitro and in vivo. Rutaecarpine is an example of biologically active constituents with anti-infl ammatory activity from natural resources, not only because it could induce some CYP enzymes, but also because its metabolic pathways including phase 1 and phase 2 have clearly been characterized (Lee et al, 2004a;2004b;2006). Meanwhile, extensive attention on possible herb-drug interaction might have not been given for this compound.…”