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The metabolic fate of tolazamide, 1-(hexahydroazepin-1-yl)-3-p-tolylsulfonylurea (1), was studied in man and in the rat using tritium-labeled 1. The metabolites were isolated in crystalline form from urine for structure determination. The crystal structure and final molecular structure of one of these, 1-(4-hydroxyhexahydroazepin-1-yl)-3-p-tolylsulfonylurea (5), were determined using single-crystal X-ray techniques. Following oral administration of tritiated tolazamide to male humans, 85% of the radioactivity was excreted in urine during a 5-day period. In addition to being excreted in urine unchanged, tolazamide was metabolized to 1-(hexahydroazepin-1-yl)-3-p-(carboxyphenyl)sulfonylurea (2), p-toluenesulfonamide (3), 1-(hexahydroazepin-1-yl)-3-p-(hydroxymethylphenyl)sulfonylurea (4), 1-(4-hydroxyhexahydroazepin-1-yl)-3-p-tolylsulfonylurea (5) and a labile, unidentified metabolite 6 by man. The relative amounts of these materials excreted in 0-24-h urine collections from eight subjects averaged 7, 17, 26, 10, 25, and 15% for 1-6, respectively. In the female rat, 79% of an orally administered dose of tritiated tolazamide was excreted in urine during a 5-day period as 1-4. The relative amounts of these materials excreted during the 24-h period following administration of tolazamide were 10, 5, 5, and 80% for 1-4, respectively.

Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide), a potent new hypotensive agent, was 14C-labeled in the 2-position of the pyrimidine ring in 17 percent yield from Ba14CO3. This material was used to study the absorption, distribution, and excretion of the drug in rats, dogs, and monkeys. Following oral administration of a single dose, the drug was rapidly and well absorbed and rapidly eliminated by each species as judged by plasma levels and urinary excretion of unchanged drug and total drug-related materials. Chronic oral administration of the drug at a high level (10 mg/kg) for 30 days slightly increased the rate of clearance of minoxidil and minoxidil-related material from circulation. Water diuresis, resulting from water loading of dogs, caused an even greater increase in the rates of disappearance of the drug and drug-related material. Whole-body autoradiography studies in rats showed that minoxidil was rapidly distributed following its oral and intravenous administration. It was subsequently concentrated, primarily in the excretory system. Minoxidil-related material was detected in aorta walls, but not in the CNS, following both routes of drug administration.

Colestipol hydrochloride, a polymeric, ion-exchange type, hypocholesterolemic agent, acting by sequestering bile acids, was labeled with carbon-14. The disposition of the labeled material was studied in the human, dog and rat. The extent of absorption from the gastrointestinal tract, as judged by urinary excretion of radioactivity, was very small and correlated well with the contents of water-soluble and dialyzable materials in the colestipol hydrochloride. Results were consistent with the dialyzable material in the drug being the absorbable species.