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 2 mM. Further study in rabbits showed that two enantiomers underwent an intermediate degree of first-pass metabolism. (−)CLA had lower concentrations and AUC 0–8h 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.