Disposition of the hypoglycaemic sulphonylurea CS 476

The disposition of radioactivity was studied after administration of a new oral hypoglycaemic agent, 14C-labelled CS 476, to rats, rabbits and dogs at a pharmacologically active dose level of 0.2 mg/kg and to human subjects at a therapeutic dose level of 5 mg. After oral doses, most of the drug was excreted in the faeces by rats and dogs and faecal radioactivity was obtained from biliary excretion. Rabbits and humans excreted most of the dose in urine. Unchanged CS 476 was the major radioactive component in the plasma of all the species during 6 hours after dosing, and was extensively bound to the plasma proteins. The half-life of CS 476 in plasma was 2 hours in dogs and humans, and 16 hours in rabbits. Drug accumulation did not occur in dog and rabbit plasma during a period of consecutive daily doses and the half-lives after the last of the repeated doses were similar to those found after single doses. In rats, plasma concentrations were relatively low, and did not reach the peak level found in female rats until 24 hours after dosing. CS 476 was extensively biotransformed. The apparent species-dependent disposition of CS 476 may explain differences in tolerance to chronic doses.