title: Stereoselective metabolism of tetrahydropalmatine enantiomers in rat liver microsomes.
abstract: Tetrahydropalmatine (THP), with one chiral center, is an active alkaloid ingredient in Rhizoma Corydalis. The aim of the present paper is to study whether THP enantiomers are metabolized stereoselectively in rat, mouse, dog, and monkey liver microsomes, and then, to elucidate which Cytochrome P450 (CYP) isoforms are predominately responsible for the stereoselective metabolism of THP enantiomers in rat liver microsomes (RLM). The results demonstrated that (+)-THP was preferentially metabolized by liver microsomes from rats, mice, dogs, and monkeys, and the intrinsic clearance (Cl(int)) ratios of (+)-THP to (-)-THP were 2.66, 2.85, 4.24, and 1.67, respectively. Compared with the metabolism in untreated RLM, the metabolism of (-)-THP and (+)-THP was significantly increased in dexamethasone (Dex)-induced and β-naphthoflavone (β-NF)-induced RLM; meanwhile, the Cl(int) ratios of (+)-THP to (-)-THP in Dex-induced and β-NF-induced RLM were 5.74 and 0.81, respectively. Ketoconazole had stronger inhibitory effect on (+)-THP than (-)-THP, whereas fluvoxamine had stronger effect on (-)-THP in untreated and Dex-induced or β-NF-induced RLM. The results suggested that THP enantiomers were predominately metabolized by CYP3A1/2 and CYP1A2 in RLM, and CYP3A1/2 preferred to metabolize (+)-THP, whereas CYP1A2 preferred (-)-THP.
authors.affiliation: Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Li
authors.forename: Dong-Li
authors.initials: DL
authors.lastname: Sun
authors.forename: Si-Yuan
authors.initials: SY
authors.lastname: Sun
authors.forename: Shan-Ding
authors.initials: SD
authors.lastname: Huang
authors.forename: Su
authors.initials: S
authors.lastname: Zeng
authors.forename: Hui-Di
authors.initials: HD
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001600:Berberine Alkaloids / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003580:Cytochromes / Q000037:antagonists & inhibitors / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004285:Dogs; D016666:Fluvoxamine / Q000494:pharmacology; D000882:Haplorhini; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008657:Metabolic Clearance Rate; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013379:Substrate Specificity; D019324:beta-Naphthoflavone / Q000494:pharmacology
chemical_list: D001600:Berberine Alkaloids; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003580:Cytochromes; D008565:Membrane Proteins; C014215:tetrahydropalmatine; D019324:beta-Naphthoflavone; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; C017170:Cyp1a2 protein, rat; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; D016666:Fluvoxamine; D007654:Ketoconazole