The Metabolism of 5-p-Aminobenzenesulphonamido-3-Methylisothiazole (Sulphasomizole)

Abstract

The fate of the sulphonamide drug, sulphasomizole, in man, dog, rabbit and rat has been studied. In man, rat and rabbit, the major urinary metabolite, is N4-acetylsulphasomizole together with the unchanged drug. In man about 60 per cent of an oral dose of 30 mg./kg. is excreted in the urine in 24 hr., just over a third being acetylated. In the rabbit about 80 per cent of an oral dose (150 mg./kg. is excreted in 24 hr. and about two-thirds is acetylated. In the rat about 70 per cent of the dose (150 mg./kg.) is excreted in 24 hr. and just under one third is acetylated. In the dog, the main excretory product is the unchanged drug, there being no acetylation. All four species excrete small amounts (1 per cent) of the N4-glucuronide of sulphasomizole. Other minor metabolites detected were the N4-sulphate of sulphasomizole which was found in rat and dog urine, and an unidentified oxidation product present as a glucuronide which was detected in rabbit and dog urine. 5-~-AMINOBENZEN~ULPHONAMIDO-~-~HYLISOTHIAZOLE (I)is an antibacterial drug containing a new heterocyclic system, namely the isothiazole or 1,2-thiazole ring system. This compound and some of its derivatives were first described by Adams and Slack (1959) and its antibacterial properties were reported by Adams and others (1960). Me __ IThe compound is marketed as a sulphonamide drug of moderateThe substance has duration of action under the name of "Bidizole". been given the approved common name, sulphasomizole. EXPERIMENTAL MaterialsSulphasomizole, m.p. 189", 5-p-aminobenzenesulphonacetamido-3-methylisothiazole (W-acetylsulphasomizole), m.p. 168-169", 5-amino-3-methylisothiazole, m.p. 41-42", 4-amino-3-hydroxybenenesulphonic acid, m.p. 266" (decomp.) and 4-amino-2-hydroxybenzenesulphonic acid were the gifts of May & Baker, Ltd., Dagenham, Essex. 5-p-Acetamidobenzenesulphonamido-3-methylisothiazole (N4-acetylsulphasomizole), m.p. 272-273" and 5-acetamid0-3-methylisothiazole, m.p. 179-180", were prepared by acetylating the corresponding amines in sodium carbonate solution with acetic anhydride (cf. Adams and Slack, 1959). 565

Species Differences in Drug Metabolism

“…A further instance of lack of acetylation capabilities of the dog was illustrated by work on sulfasomizole (5-p-aminobenzenesulfonamido-3-methylisothiazole) which is acetylated in man, rat, and rabbit, but not in the dog (179).…”