Absorption, distribution, and metabolic fate of 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo-(3,2-b)(1,3)-benzoxazin-9-one in rats, dogs, and humans.
The absorption and metabolic fate of 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo-(3,2-b)(1,3)-benzoxazin-9-one (I) was studied in rats, dogs, and humans. Orally administered I was readily absorbed by all species. In the rat, orally administered I was converted to its metabolite, 5-chlorosalicylic acid, by the intestinal wall. The half-lives of blood radioactivity, after the oral administration of I-9-14C, were about 18 and 12 hr in the rat and beagle hound, respectively. In human subjects, no intact I was detected in the bloodstream; however, the clearance of the metabolite, 5-chlorosalicylic acid, had a half-life of about 33 hr. Cleavage of the oxazine ring of I generated 5-chlorosalicylic acid, which was excreted both in the free form and conjugated with glycine and glucuronic acid. The isoxazole moiety was converted to beta-hydroxybutyric acid and its metabolites carbon dioxide and fumaric, citric, alpha-ketoglutaric, succinic, and malic acids. Binding of I to plasma proteins was extensive but was less than that of 5-chlorosalicylic acid.
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D004285:Dogs; D004355:Drug Stability; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007555:Isoxazoles / Q000378:metabolism*; D008297:Male; D010078:Oxazines / Q000378:metabolism*; D010080:Oxazoles / Q000378:metabolism*; D011485:Protein Binding; D011865:Radioisotope Dilution Technique; D051381:Rats; D012459:Salicylates / Q000302:isolation & purification; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D007555:Isoxazoles; D010078:Oxazines; D010080:Oxazoles; D012459:Salicylates