title: Disposition and metabolism of 2,6-dimethylbenzamide N-(5-methyl-3-isoxazolyl) (D2916) in male and female rats.
abstract: Disposition and metabolism of the new anticonvulsant 2,6-dimethylbenzamide N-(5-methyl-3-isoxazolyl) (D2916) was studied in male and female rats after oral administration of 14C-labeled material. D2916 was well absorbed in both sexes and distributed to all tissues, with maximal drug concentrations found in elimination and metabolization organs, as well as in fatty tissues. Striking differences in pharmacokinetic parameters of total radioactivity were observed between males and females; females had higher brain concentrations and longer blood and tissue half-lives. The study of blood, bile, urine, and brain metabolites showed that D2916 follows two degradation pathways related to hydroxylation of methyl groups. Males prefer to hydroxylate one of the methyl groups of the phenyl ring, and females prefer to hydroxylate the methyl of the isoxazolyl ring forming the active metabolite D3187. These findings suggest a sex difference in the location of the hydroxylation of the D2916 molecule and can explain the longer anticonvulsant effect observed in the female rat that is related both to an orientation of the metabolism toward the formation of the active metabolite and to a better ability to this metabolite to cross the blood-brain barrier, compared with the unchanged drug.
authors.affiliation: INSERM U71, Clermont-Ferrand, France.
authors.forename: J C
authors.initials: JC
authors.lastname: Maurizis
authors.forename: J C
authors.initials: JC
authors.lastname: Madelmont
authors.forename: M
authors.initials: M
authors.lastname: Rapp
authors.forename: C
authors.initials: C
authors.lastname: Marijnen
authors.forename: M C
authors.initials: MC
authors.lastname: Cerf
authors.forename: J M
authors.initials: JM
authors.lastname: Gillardin
authors.forename: F
authors.initials: F
authors.lastname: Lepage
authors.forename: A
authors.initials: A
authors.lastname: Veyre
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000737:chemistry; D001923:Brain Chemistry; D002250:Carbon Radioisotopes; D005243:Feces / Q000737:chemistry; D005260:Female; D007555:Isoxazoles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D014018:Tissue Distribution
chemical_list: D000927:Anticonvulsants; D002250:Carbon Radioisotopes; D007555:Isoxazoles; C105493:soretolide