Pharmacokinetics and metabolism of clausenamide enantiomers (1064.4)

Abstract

The properties of (‐) and (+)clausenamide(CLA) in pharmacokinetics and metabolism were investigated in rats and rabbits. There were several main findings obtained from these studies: (1) (+)CLA exhibited greater tmax(35.0±12.2 min, p<0.01), Cmax (26.1±7.1μg/ml), t1/2β(217.2±34.2min, p<0.01), AUC0‐12h (2446.0±540.4 min/μg/ml, p<0.001), and smaller CL/F(0.063±0.017 l/kg/min, p<0.001) and Vd/F(20.0±7.8 l/kg, p<0.01), than (‐)CLA after oral administration to rats. The (+)/(‐)‐isomer ratios for tmax, Cmax, t1/2β, AUC0‐12 h, CL/F, and Vd/F were 1.75, 1.21, 1.26, 1.95, 0.47, and 0.59, respectively; (2) the binding of (+)CLA to rat plasma protein (38.0%±2.6%) was significantly greater than that of (‐)CLA (28.5 %±0.6%); and there were significant species differences in the plasma protein binding of (‐)CLA between rabbits(47.2 %±4.9 %) and rats. (3) (‐)CLA had a more rapid absorption and distribution to rat hippocampus, cortex, and cerebellum with smaller values for tmax, t1/2β, and AUC0→∞, and greater ones for CL/F and Vd/F than its antipode. (4) (‐)CLA was mainly excreted in feces with 13.9% of dose, whereas (+)CLA in bile with 17.2%; (5) in the in vitro metabolic system, (‐)CLA was mainly metabolized to 7‐hydroxy‐, 5‐hydoxy‐ and 4‐hydroxy‐CLA, and 7‐hydroxylation was a preferential pathway , but (+)CLA was mainly metabolized to 4‐hydroxy‐CLA, its 7‐hydroxyl and 4‐hydroxyl metabolites were very small; (6)the major metabolic enzyme for CLA enantiomers was CYP3A isoforms whose expression could be induced by (‐)‐isomer in the rat liver. (7) both (‐) and (+)CLA were subjected to an intermediate degree of first‐pass metabolism in rabbits with rates of hepatic extraction 64.7% for (‐)‐isomer and 50.8% for (+)‐isomer. These data suggested that there were markedly stereoselective differences in pharmacokinetics and metabolism between two enantiomers, which may be important in understanding the clinic pharmacology of active eutomer, (‐)CLA, for treatment of Alzheimer’s disease.Grant Funding Source: grants from the National Natural Science Foundation of China (29790120; 30873117).