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KMID : 0043320110340081311
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Archives of Pharmacal Research
2011 Volume.34 No. 8 p.1311 ~ p.1321
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Metabolism of dl-praeruptorin a in rat liver microsomes using HPLC-electrospray ionization tandem mass spectrometry
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Ruan Hang
Zhang Zhen
Liang Xin fang
Fu Yan
Su Mei qin
Liu Qi lin
Wang Xiu min
Zhu Xuan
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Abstract
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dl-Praeruptorin A (Pd-Ia) is the major active constituent of the traditional Chinese medicine Peucedanum praeruptorum Dunn. Recently it has been identified as a novel agent in the treatment and prevention of cardiovascular diseases. Accordingly, we investigated the metabolism of Pd-Ia in rat liver microsomes. The involvement of cytochrome P450 (CYP) and CYP isoforms were identified using a CYP-specific inhibitor (SKF-525A), CYP-selective inhibitors (α-naphthoflavone, metyrapone, fluvastatin, quinidine, disulfiram, ketoconazole and ticlopidine) and CYP-selective inducers (phenobarbital, dexamethasone and β-naphthoflavone). Residual concentrations of the substrate and metabolites were determined by HPLC, and further identified by their mass spectra and chromatographic behavior. These experiments showed that CYP450 is involved in Pd-Ia metabolism, and that the major CYP isoform responsible is CYP3A1/2, which acts in a concentration-dependent manner. Four Pd-Ia metabolites (M1, M2, M3, and M4) were detected after incubation with rat liver microsomes. Hydroxylation was the primary metabolic pathway of Pd-Ia, and possible chemical structures of the metabolites were identified. Further research is now needed to link the metabolism of Pd-Ia to its drug-drug interactions.
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KEYWORD
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dl-Praeruptorin A, Cytochrome P450 isoforms, Metabolites, Rat liver microsomes, In vitro, HPLC-ESI-MSn
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