کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2480868 | 1556206 | 2013 | 6 صفحه PDF | دانلود رایگان |
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 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.
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Journal: European Journal of Pharmaceutical Sciences - Volume 49, Issue 4, 16 July 2013, Pages 761–766