title: Effect of the oral absorption of benzenesulfonanilide-type cyclooxygenase-1 inhibitors on analgesic action and gastric ulcer formation.
abstract: A benzensulfonanilide-type cyclooxygenase-1 (COX-1)-selective inhibitor, ZXX2-77: 4-amino-4'-chloro-N-methylbenzenesulfonanilide (4a), has been reported as a novel analgesic that does not cause gastric damage. This compound has a weak analgesic effect but has potent in vitro COX-1 inhibitory activity. Since the reason for the weak analgesic effect in vivo was thought to be the low rate of oral absorption, the blood concentration of ZXX2-77 (4a) was measured in rats. It was found that the C(max) value (1.2 microM) of ZXX2-77 (4a) at a dose of 30 mg/kg did not reach the COX-1 IC(50) value (3.2 microM). On the other hand, ZXX2-79 (4b) (SO(2)NH derivative of ZXX2-77 (4a); 4-amino-4'-chlorobenzenesulfonanilide), which shows less potent COX inhibitory activities (COX-1 IC(50) = 12 microM, COX-2 IC(50) = 150 microM) than those of ZXX2-77 (4a) in vitro, was found to be more absorbable (C(max) = 16 microM at a dose of 30 mg/kg in rats) than ZXX2-77 (4a). Furthermore, ZXX2-79 (4b) not only showed a potent analgesic effect in a formalin test but also caused little gastric damage. These findings indicate that demethylated sulfonamide compounds are more easily absorbed than are N-methylated sulfonamide compounds and suggest that COX-1-selective inhibitors will be useful as analgesics that do not cause gastric damage.
authors.affiliation: Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-Naka, Okayama 700-8530, Japan.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zheng
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Oda
authors.forename: Shun
authors.initials: S
authors.lastname: Harada
authors.forename: Yukio
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tai
authors.forename: Kenji
authors.initials: K
authors.lastname: Sasaki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakuta
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D017207:Rats, Sprague-Dawley; D013276:Stomach Ulcer / Q000517:prevention & control*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D000700:Analgesics; D016861:Cyclooxygenase Inhibitors; D013449:Sulfonamides; D000096926:Benzenesulfonamides