title: Stereoselective pharmacokinetics of clausenamide enantiomers and their major metabolites after single intravenous and oral administration to rats.
abstract: The pharmacokinetics of clausenamide (CLA) enantiomers and their metabolites were investigated in Wistar rat. After intravenous and oral administration at a dose of 80 and 160 mg/kg each enantiomer, plasma concentrations of (-)- or (+)-CLA and its major metabolites were simultaneously determined by reverse-phase HPLC with UV detection. Notably, stereoselective differences in pharmacokinetics were found. The mean plasma levels of (+)-CLA were higher at almost all time points than those of (-)-CLA. (+)-CLA also exhibited greater t(max), C(max), t(1/2beta), AUC(0-12h), and AUC(0--> infinity) and smaller CL (or CL/F) and V(d) (or V(d)/F), than its antipode. The (+)/(-) isomer ratios for t(1/2beta), t(max), AUC(0-12 h), and AUC(0--> infinity), which ranged from 1.26 to 2.08. The ratio for CL (or CL/F) was about 0.5, and there were significant differences in these values between CLA enantiomers (P < 0.05), implying that the absorption, distribution, and elimination of (-)-CLA were more rapid than those of (+)-CLA. Similar findings for (-)-7-OH-CLA, the major metabolite of (-)-CLA, and (+)-4-OH-CLA, the major metabolite of (+)-CLA, can be also seen in rat plasma. The contributing factors for the differences in stereoselective pharmacokinetics of CLA enantiomers appeared to be involved in their different plasma protein binding, first-pass metabolism and interaction with CYP enzymes, especially with their metabolizing enzyme CYP 3A isoforms.
authors.affiliation: Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Chuan Jiang
authors.initials: CJ
authors.lastname: Zhu
authors.forename: Jun Tian
authors.initials: JT
authors.lastname: Zhang
mesh_terms: D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D001711:Biotransformation; D005260:Female; D006207:Half-Life; D007275:Injections, Intravenous; D007769:Lactams / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D017705:Lignans / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
chemical_list: D007769:Lactams; D017705:Lignans; C053048:clausenamide