title: Stereoselective excretion and first-pass metabolism of clausenamide enantiomers.
abstract: Stereoselective differences in pharmacokinetics between clausenamide (CLA) enantiomers have been found after intravenous and oral administration of each enantiomer to rats. The differences could be associated with excretion and first-pass metabolism of two enantiomers. The data from this study demonstrated that (-)CLA was mainly excreted in feces with 13.9% of dose, whereas (+)CLA in bile with 17.2%. A large portion of CLA enantiomers could be transformed into hydroxyl metabolites. In the in vitro metabolic system using rat liver microsomes, it was found that (-)CLA was cleared more than its antipode with peak height ratios [(+)/(-)] from 1.0 to 1.8 at the corresponding substrate concentrations from 0.25 to 2mM. Further study in rabbits showed that two enantiomers underwent an intermediate degree of first-pass metabolism. (-)CLA had lower concentrations and AUC0-8h in the portal vein and heart than those of (+)CLA with rates of hepatic extraction 64.7% for (-)-isomer and 50.8% for (+)-isomer, and intrinsic metabolic clearances of (-) and (+)CLA being 186.3 and 107.2 (l/h), respectively. The first-pass metabolism was involved in CYP3A enzymes in the gut and liver, and different levels of CYP3A1 expression induced by (-)CLA or (+)CLA. Immunohistochemical analyses revealed that (-)-isomer significantly increased the expression of CYP3A1, while (+)-isomer had no obvious effects on it. Taken together, the results provided new evidence that stereoselective pharmacokinetics of CLA enantiomers could be resulted from their stereoselective excretion, first-pass metabolism and induction to metabolizing enzymes, which might be important in understanding the clinic pharmacology of active eutomer, (-)CLA, for treatment of Alzheimer's disease.
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. zhucj@imm.ac.cn
authors.forename: Chuan-jiang
authors.initials: CJ
authors.lastname: Zhu
authors.forename: Ling-juan
authors.initials: LJ
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Hua
authors.forename: Xiao-ming
authors.initials: XM
authors.lastname: Yu
authors.forename: Jun-tian
authors.initials: JT
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001646:Bile / Q000737:chemistry; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005260:Female; D007769:Lactams / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D017705:Lignans / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
chemical_list: D007769:Lactams; D017705:Lignans; C053048:clausenamide; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A
keywords: Clausenamide enantiomers; Cytochrome P450 3A; Excretion; First-pass effect; Metabolism; Stereoselectivity