The metabolic fate of supidimide in the rat

The absorption, metabolism and excretion of 3-(2,3-dihydro-1,1-dioxido-3-oxo-1,2-benzisothiazol-2-yl)-2-oxopiperidine (supidimide) in the rat are investigated. Following oral administration of 35S-labelled supidimide (12.5 and 25 mg/kg), the radioactivity is rapidly absorbed and excreted almost quantitatively within 72 h. 85% of the radioactivity administered is recovered from urine. In the faeces a further 14% is found predominantly resulting from biliary excretion. Excretion rates of urinary radioactivity show a 2-phase course with half-lives of 2.6 h and 10 h. Unchanged supidimide is eliminated with a half-life of 2.1 h. A total of 10 metabolites are identified in urine, faeces or in vitro systems and quantified. Identification of the metabolites is achieved by co-crystallization or co-chromatography with synthetic reference compounds, chemical analysis, mass spectrometry or combinations of these techniques. The pattern of metabolites observed in vivo and in vitro studies reveal that supidimide is primarily oxidized in the piperidone moiety of the molecule by the microsomal drug metabolizing system. Largely spontaneous hydrolysis of preexisting or newly formed carbonamide bonds gives rise to the variety of metabolic products. Hydrolysis of the sulfonamide bond and oxidation of the benzene moiety are not detectable. Only after subchronic treatment with an elevated dosage of supidimide (greater than or equal to 150 mg/kg) is a reversible induction of cytochrome P-450 observed.