title: CYP3A catalyses schizandrin biotransformation in human, minipig and rat liver microsomes.
abstract: Schizandrin is recognized as the major absorbed effective constituent of Fructus schisandrae, which is extensively applied in Chinese medicinal formula. The present study aimed to profile the phase I metabolites of schizandrin and identify the cytochrome P450 (CYP) isoforms involved. After schizandrin was incubated with human liver microsomes, three metabolites were isolated by high-performance liquid chromatography (HPLC) and their structures were identified to be 8(R)-hydroxyl-schizandrin, 2-demethyl-8(R)-hydroxyl-schizandrin, 3-demethyl-8(R)-hydroxyl-schizandrin, by liquid chromatography-mass spectrometry (LC-MS), (1)H-nuclear magnetic resonance (NMR), and (13)C-NMR, respectively. A combination of correlation analysis, chemical inhibition studies, assays with recombinant CYPs, and enzyme kinetics indicated that CYP3A4 was the main hepatic isoform that cleared schizandrin. Rat and minipig liver microsomes were included when evaluating species differences, and the results showed little difference among the species. In conclusion, CYP3A4 plays a major role in the biotransformation of schizandrin in human liver microsomes. Minipig and rat could be surrogate models for man in schizandrin pharmacokinetic studies. Better knowledge of schizandrin's metabolic pathway could provide the vital information for understanding the pharmacokinetic behaviours of schizandrin contained in Chinese medicinal formula.
authors.affiliation: School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Y-F
authors.initials: YF
authors.lastname: Cao
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: G-B
authors.initials: GB
authors.lastname: Ge
authors.forename: D
authors.initials: D
authors.lastname: Hu
authors.forename: H-X
authors.initials: HX
authors.lastname: Liu
authors.forename: T
authors.initials: T
authors.lastname: Huang
authors.forename: Y-C
authors.initials: YC
authors.lastname: Wang
authors.forename: Z-Z
authors.initials: ZZ
authors.lastname: Fang
authors.forename: D-X
authors.initials: DX
authors.lastname: Sun
authors.forename: H
authors.initials: H
authors.lastname: Huo
authors.forename: J
authors.initials: J
authors.lastname: Yin
authors.forename: L
authors.initials: L
authors.lastname: Yang
mesh_terms: D000818:Animals; D002384:Catalysis / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D034242:Cyclooctanes / Q000737:chemistry / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D017705:Lignans / Q000737:chemistry / Q000493:pharmacokinetics*; D013058:Mass Spectrometry; D053858:Metabolic Networks and Pathways; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D011083:Polycyclic Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D013552:Swine; D013556:Swine, Miniature; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: D034242:Cyclooctanes; D065692:Cytochrome P-450 CYP3A Inhibitors; D017705:Lignans; D011083:Polycyclic Compounds; D014217:Troleandomycin; D051544:Cytochrome P-450 CYP3A; C011105:schizandrin; D007654:Ketoconazole