Streptozotocin: its excretion and metabolism in the rat.

The excretion of radioisotope following the administration of three specifically 14C-labelled forms of streptozotocin was investigated in the rat using ureter and bile duct cannulation techniques. The urine collected during the first hour following the administration of the drug contained the highest proportion of injected radioactivity (approximately 34% with (3'-methyl-14C)-streptozotocin and approximately 40% each with (1-14C)-and (2'-14C)-streptozotocin. Over the entire experimental period (6 hours), approximately 70% of the injected radioactivity of (1-14C)- and (2'-14C)-streptozotocin appeared in the urine. With (3'-methyl-14C)-streptozotocin, only 53% of the injected radioactivity appeared in the urine over the same period. In contrast to the high urinary excretion, less than 3% of the injected radioactivity from all three radiolabelled streptozotocin samples appeared in the bile. The in vivo and in vitro metabolism of streptozotocin was also investigated. In addition to substantial amounts of unchanged drug, three radiolabelled metabolites (two major and one minor) were detected in the urine during the 6 hour collection period following the administration of (1-14C)- and (2'-14C)-streptozotocin. In contrast, only unchanged (3'-methyl-14C)-streptozotocin was detected in the urine collected over the same period following the administration of the methyl labelled drug. The two major metabolites were also produced when (1-14C)-and (2'-14C)-streptozotocin were incubated with a rat liver supernatant fraction (100,000 X g). The liver was further demonstrated to be the major site of metabolism in isolated liver perfusion studies in which both (1-14C)- and (2'-14C)-streptozotocin were quantitatively converted to the two major metabolites. The two major metabolites of (1-14C)-streptozotocin, whether produced in vivo or in vitro, were chromatographically homogenous with the two major metabolites formed from (2'-14C)-streptozotocin. Nicotinamide pretreatment had no apparent effect on the urinary excretion of streptozotocin and its metabolites.