STEREOSELECTIVE METABOLISM OF A NEW ANTICONVULSANT DRUG CANDIDATE, LOSIGAMONE, BY HUMAN LIVER-MICROSOMES

Losigamone (LSG) is a new candidate anticonvulsant drug undergoing pre clinical and clinical development. Metabolism of racemic (+/-)-LSG and its two enantiomers, AO-242 [(+)-LSG] and AO-294 [(-)-LSG], was studi ed using human liver microsomes and recombinant cytochrome P450 isozym es. HPLC with both UV and electrochemical detection was used for analy sis of the incubation media. Five metabolites (M1, M2, M3, M4, and M5) were generated from racemic (+/-)-LSG by both human liver microsomes and recombinant enzymes. Stereoselective metabolism was observed when each enantiomer was incubated separately with human liver microsomes. M1 was the major metabolite produced from (+)-LSG, whereas M3, M4, and M5 were primarily produced from (-)-LSG. The production of M1 from ()-LSG was markedly inhibited by (-)-LSG, indicating a metabolic enanti omer/enantiomer interaction. (+/-)-LSG enantiomers were selectively me tabolized by recombinant cytochrome P450 2A6, and the metabolism of ()-LSG and (-)-LSG by human liver microsomes was preferentially inhibit ed by coumarin, a cytochrome P450 2A6-selective compound.