Stereoselective metabolism of tetrahydropalmatine enantiomers in rat liver microsomes

• Published in: Chirality (New York, N.Y.) Vol. 24; no. 5; pp. 368 - 373
• Main Authors: Zhao, Ming, Li, Li-Ping, Sun, Dong-Li, Sun, Si-Yuan, Huang, Shan-Ding, Zeng, Su, Jiang, Hui-Di
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.05.2012
• Subjects: Animals; Berberine Alkaloids - chemistry; Berberine Alkaloids - metabolism; Berberine Alkaloids - pharmacokinetics; beta-Naphthoflavone - pharmacology; CYP1A2; CYP3A1/2; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; Cytochromes - antagonists & inhibitors; Cytochromes - metabolism; Dexamethasone - pharmacology; Dogs; Fluvoxamine - pharmacology; Haplorhini; Ketoconazole - pharmacology; liver microsomes; Male; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - metabolism; Metabolic Clearance Rate; Mice; Mice, Inbred ICR; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Rats; Rats, Sprague-Dawley; Stereoisomerism; stereoselective metabolism; Substrate Specificity; tetrahydropalmatine
• ISSN: 0899-0042; 1520-636X
• DOI: 10.1002/chir.22020

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 (Clint) 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 Clint 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. Chirality 24:368–373, 2012. © 2012 Wiley Periodicals, Inc.