title: Pharmacokinetics and metabolism of jatrorrhizine, a gastric prokinetic drug candidate.
abstract: Jatrorrhizine, a protoberberine alkaloid derived from Coptis chinensis, is currently under investigation as a natural gastric prokinetic drug candidate. In vitro and in vivo studies were conducted to characterize its pharmacokinetics and metabolism. After intravenous administration, the plasma concentration kinetics and major metabolites in rats were investigated. The metabolic kinetics, key cytochrome P450 enzymes and UDP-glucuronosyltransferase isoforms (UGTs) of jatrorrhizine were studied in rat liver microsomes (RLMs). After intravenous administration, plasma jatrorrhizine concentrations showed a biphasic decline, dose-independent clearance and half-life of terminal elimination phase, and a relatively large distribution volume. The metabolic pathway for the conversion of jatrorrhizine was important for its elimination. In addition, the demethylated and glucuronidated products were found to be the major metabolites in rats. The enzyme kinetics for both demethylation and glucuronidation were fitted to the hyperbolic Michaelis-Menten equation in RLMs. CYP3A1/2 and CYP2D2 were mainly responsible for demethylation, and UGT 1A1 and 1A3 were responsible for glucuronidation in RLMs. The metabolic properties of jatrorrhizine suggest multiple metabolic pathways. These results will contribute to promote further research and development of jatrorrhizine.
authors.affiliation: Laboratory of Pharmacokinetics, Department of Chemistry, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Shi
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.forename: Bingliang
authors.initials: B
authors.lastname: Ma
authors.forename: Yueming
authors.initials: Y
authors.lastname: Ma
authors.forename: Dazheng
authors.initials: D
authors.lastname: Wu
authors.forename: Xinhong
authors.initials: X
authors.lastname: Wang
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Luo
authors.forename: Nengneng
authors.initials: N
authors.lastname: Cheng
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001599:Berberine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D005765:Gastrointestinal Agents / Q000097:blood / Q000493:pharmacokinetics*; D014453:Glucuronosyltransferase / Q000378:metabolism; D006207:Half-Life; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000099148:UGT1A1 Enzyme
chemical_list: D001599:Berberine; D003577:Cytochrome P-450 Enzyme System; D005765:Gastrointestinal Agents; D014453:Glucuronosyltransferase; C499946:Ugt1a1 protein, rat; D000099148:UGT1A1 Enzyme; C055785:jatrorrhizine