PHARMACOKINETICS OF [C-14]-LABELED LOSIGAMONE AND ENANTIOMERS AFTER ORAL-ADMINISTRATION TO HEALTHY-SUBJECTS

Losigamone R,S*)-5-(2-chlorophenylhydroxymethyl)-4-methoxy-2 (SH)-fur anone; AO-33) is a new potential antiepileptic drug undergoing clinica l development. In a crossover study, 200 mg [C-14]-labelled Losigamone , as well as 100 mg of each of the unlabelled enantiomers, was adminis tered to 5 healthy volunteers as an oral suspension. The objectives of the study were to determine the mode of elimination, the excretion ba lance, metabolic profile, the in vitro and in vivo binding to plasma p roteins and the pharmacokinetics of both enantiomers in plasma. From t he plasma concentration-time profiles of [C-14]-radioactivity and unch anged Losigamone it can be concluded that the absorption of Losigamone occurs very rapidly and the plasma concentration of the parent compou nd versus total radioactivity was consistently about 40%. An overall r ecovery of total radioactivity of about 97% with 85% in urine and 12% in faeces was found. Protein binding was 50%. Losigamone was extensive ly metabolized, with only traces of unchanged drug found in urine. The predominant metabolic pathways are hydroxylation and conjugation. Aft er administration of the pure enantiomers, significant differences in pharmacokinetics were observed. The mean oral clearance of the (-)-ena ntiomer was 1863 ml/min and of the (+)-enantiomer was 171 ml/min. Ther e was no chiral inversion after administration of the enantiomers.