Stereoselective Pharmacokinetics of the Four Stereoisomers of 4-(Dimethylamino)-2-phenyl-2-(2-pyridyl)pentanamide in Rats

The stereoselective pharmacokinetics of the four stereoisomers [FK176 (2R, 4R- and 2S, 4S-isomer) and FK177 (2R, 4S- and 2S, 4R-isomer)] of 4-(dimethylamino)-2-phenyl-2-(2-pyridyl)pentanamide were studied in rats. 1. When racemic FK176 (vamicamide) was orally administered to rats at 10 mg/kg, there were no stereoselective differences in the pharmacokinetics of 2R, 4R and 2S, 4S-enantiomer. 2. When racemic FK177 was orally administered to rats at 10 mg/kg, the mean Cmax and AUC values for the 2R, 4S-enantiomer were 2.0 and 3.0 times greater, respectively, than those for the 2S, 4R-enantiomer. 3. Serum protein binding of four stereoisomers were very low and there was no appreciable difference. 4. Rat hepatic microsomes metabolized 2S, 4R-isomer faster than 2R, 4R-, 2S, 4S and 2R, 4S-isomer. 2S, 4R-isomer was mainly metabolized to aryl hydroxylated metabolite. 5. Eight metabolites, M-I to M-V and M-B to M-D, were isolated from bile samples collected from rats after oral administration of FK176 or 2S, 4R-isomer. The structures of these metabolites were characterized by mass spectrometry and were comfirmed by comparison with reference compounds. 6. Finally, we concluded that the stereoselective differences in serum levels of 2S, 4R isomer were caused by stereoselective hepatic metabolism.