DISPOSITION AND METABOLISM OF 2,6-DIMETHYLBENZAMIDE N-(5-METHYL-3-ISOXAZOLYL) (D2916) IN MALE AND FEMALE RATS

Disposition and metabolism of the new anticonvulsant 26-dimethylbenzam ide N-(5-methyl-3-isoxazolyl) (D2916) was studied in male and female r ats after oral administration of C-14-labeled material. D2916 was well absorbed in both sexes and distributed to all tissues, with maximal d rug concentrations found in elimination and metabolization organs, as well as in fatty tissues, Striking differences in pharmacokinetic para meters of total radioactivity were observed between males and females: females had higher brain concentrations and longer blood and tissue h alf-lives. The study of blood, bile, urine, and brain metabolites show ed that D2916 follows two degradation pathways related to hydroxylatio n of methyl groups. Males prefer to hydroxylate one of the methyl grou ps of the phenyl ring, and females prefer to hydroxylate the methyl of the isoxazolyl ring forming the active metabolite D3187. These findin gs suggest a sex difference in the location of the hydroxylation of th e D2916 molecule and can explain the longer anticonvulsant effect obse rved in the female rat that is related both to an orientation of the m etabolism toward the formation of the active metabolite and to a bette r ability to this metabolite to cross the blood-brain barrier, compare d with the unchanged drug.