Characterization of metabolites of tanshinone IIA in rats by liquid chromatography/tandem mass spectrometry

Abstract

The metabolism of tanshinone IIA was studied in rats after a single-dose intravenous administration. In the present study, 12 metabolites of tanshinone IIA were identified in rat bile, urine and feces with two LC gradients using LC-MS/MS. Seven phase I metabolites and five phase II metabolites of tanshinone IIA were characterized and their molecular structures proposed on the basis of the characteristics of their precursor ions, product ions and chromatographic retention time. The seven phase I metabolites were formed, through two main metabolic routes, which were hydroxylation and dehydrogenation metabolism. M1, M4, M5 and M6 were supposedly tanshinone IIB, hydroxytanshinone IIA, przewaquinone A and dehydrotanshinone IIA, respectively, by comparing their HPLC retention times and mass spectral patterns with those of the standard compounds. The five phase II metabolites identified in this research were all glucuronide conjugates, all of which showed a neutral loss of 176 Da. M9 and M12 were more abundant than other identified metabolites in the bile, which was the main excretion path of tanshinone IIA and the metabolites. M12 was the main metabolite of tanshinone IIA. M9 and M12 were proposed to be the glucuronide conjugates of two different semiquinones and these semiquinones were the hydrogenation products of dehydrotanshinone IIA and tanshinone IIA, respectively. This hydrogenized reaction may be catalyzed by the NAD(P)H: quinone acceptor oxidoreductase (NQO). The biotransformation pathways of tanshinone IIA were proposed on the basis of this research.

Regioselective Glucuronidation of Tanshinone IIa after Quinone Reduction: Identification of Human UDP-Glucuronosyltransferases, Species Differences, and Interaction Potential

“…1. The predominant metabolites M1 (R t , 12.1 min) and M2 (R t , 12.6 min) were characterized as the two glucuronides of the quinone-reduced TSA at the C-10 or C-11 position by product ion scan, neutral loss scan, and glucuronidase hydrolysis based on the method of our previous reports (Li et al, 2005(Li et al, , 2006Hao et al, 2006bHao et al, , 2007. It was found that TSA underwent quinone reduction and subsequent glucuronidation metabolism in the liver S9 systems of all the species studied here and also in the intestinal S9 of rat and mouse.…”

“…NAD(P)H:quinone oxidoreductase 1 (NQO1)-catalyzed quinone reduction, producing a highly unstable catechol intermediate followed by an immediate glucuronidation, was identified as the predominant metabolic pathway of TSA in rats (Hao et al, 2007). Although some hydroxylated metabolites were identified from rat bile samples and in vitro liver microsomal incubation medium, most hydroxylated metabolites also underwent further quinone reduction and subsequent glucuronidation (Li et al, 2006). Such a metabolic pathway has been confirmed with other tanshinones such as cryptotanshinone (Dai et al, 2008) and dihydrotanshinone I (Liu et al, 2007).…”

Study of tanshinone IIA tissue distribution in rat by liquid chromatography‐tandem mass spectrometry method

“…These HPLC methods had a run time of about 20 min per sample. Several LC/MS/ MS methods with a run time of 7-12 min have also been used to determine tanshione IIA in different biological matrices such as the plasma Hao et al, 2006), rat liver microsome (Li et al, , 2006a and rat bile (Li et al, 2006c).…”

Effects of Salvia miltiorrhiza on CNS Neuronal Injury and Degeneration: A Plausible Complementary Role of Tanshinones and Depsides

“…Concerning the pharmacokinetic of tashinones, there are several studies available in the literature on single tanshinones showing that CTS was metabolized to a major metabolite, TSIIA, and trace amounts of several hydroxyl-and dihydroxyl-CTS derivatives in rats [77][78][79][80]. Some showed that TSIIA was metabolized to TSIIB, and some hydroxylated derivatives, dehydrotanshinone IIA and tanshinaldehyde in rats [77,80,81]. It was also shown that DTSI was metabolized to TSI by dehydrogenation, hydroxyl derivatives, and a derivative by D-ring hydrolysis in rats [80].…”