The Fate of Saccharin Impurities: The Excretion and Metabolism of [3-¹⁴C]Benz[d]-isothiazoline-1,1-dioxide (BIT) in Man and Rat

Abstract

1. The ¹⁴C label of [3-¹⁴C]benz[d] isothiazoline-1, 1-dioxide (BIT) (40 mg/kg) was rapidly eliminated (97% dose in 24 h), largely in the urine (92% dose in 24 h), after oral administration to rats. Larger doses (400 mg/kg) were eliminated more slowly after oral or parenteral administration (45-60% within 24 h) mostly in the urine (42-53%). Little ¹⁴C (2-3% dose) was present in the faeces after intraperitoneal (400 mg/kg) or low oral (40 mg/kg) doses, but the presence of larger amounts (12% dose) after larger oral doses (400 mg/kg) indicated incomplete absorption.

2. Metabolites identified in the urine of rats were saccharin (about 30% of urinary ¹⁴C), 2-sulphamoylbenzoic acid (about 35% urinary ¹⁴C) and 2-sulphamoylbenzyl alcohol (15% urinary ¹⁴C) in addition to unchanged compound (5-10% urinary ¹⁴C). The urine also contained a polar, labile metabolite that gave BIT on acid hydrolysis. The pattern of metabolism was not significantly affected by dose or route of administration.

3. In man, urine was the major route of elimination of ¹⁴C (93% dose) after administration of ¹⁴C-BIT (0·5 mg/kg). Negligible ¹⁴C was recovered in the faeces (<1% dose). Excretion was rapid (59% dose in 6 h; 80% dose in 12 h) and little ¹⁴C was eliminated on the second (3%) or subsequent days after dosing.

4. Identified metabolites in man included saccharin (about 50% of urinary ¹⁴C), 2-sulphamoylbenzoic acid (7% urinary ¹⁴C) and 2-sulphamoylbenzyl alcohol (8% urinary ¹⁴C unconjugated and 40% conjugated) with negligible unchanged compound. Only traces of the polar labile metabolite were detected.

5. The possible significance of metabolic interrelationships of toluene-2-sulphonamide and BIT to studies on the metabolism of saccharin are discussed.