Studies On Pharmacokinetics And Enzymatic Kinetics Of Clausenamide Enantiomers

Clausenamide(clau), a novel nootropic compound, was isolated from the leaves of Clausena lansium (Lour) skeels. Its chemical structure contains four asymmetric carbons with eight pair of enantiomers. The absolute configurations of (-)clau and (+)clau are 3S,4R,5R,7S and 3R,4S,5S,7S,respectively. It exists in plant as a racemate, and now both (-) and (+)clau can be synthesized and resoluted by chemists in our institute. This provides us great convenience on the study of each isomer of clau. The present paper deals with the pharmacokinetics and enzymatic kinetics of clau enantiomers in rats.Part one Pharmacokinetics of Clausenamide EnantiomersIn biological system, macromolecules such as protein, polynucleotide, glycolipid constitute internal chiral surroundings, which can discriminate and interact with enantiomers.In this case stereoselective pharmacokinetics and stereoselective pharmacodynamics of chiral drugs can be produced.The pharmacokinetics of clau enantiomers in rat plasma showed markedly stereoselective. Afte intravenous or oral administration to Wistar rats at three different doses of each enantiomer(20-160 mg ? kg^-1), plasma concentrations of (-) or (+)clau and its main metabolites were simultaneously determined by reverse phase HPLC with UV detector; Pharmacokinetic analysis indicated that (+)clau was found to have significantly higher t_1/2α,t_1/2β, t_1/2ka, T_max, C_max, AUC_0-t, and lower V_d, and CL than those of (-)clau. This results implied that the absorption of (-)clau was more rapid and so was the clearance. In addition, main metabolite,4-OH-clau(CM₃), of (+)clau had similar findings with higher...