COMPARATIVE METABOLISM OF TOLBUTAMIDE BY ISOLATED HEPATOCYTES FROM RAT, RABBIT, DOG, AND SQUIRREL-MONKEY

  • 1 January 1984
    • journal article
    • research article
    • Vol. 12  (2) , 174-178
Abstract
Tolbutamide (TB; 1-butyl-3-p-tolylsulfonylurea) [a hypoglycemic drug] was used for metabolism studies with hepatocytes isolated from the rat, rabbit, dog and squirrel monkey to validate their usefulness as models for comparative in vivo metabolism. Hepatocytes were prepared by whole liver or biopsy perfusion. TB (3 .times. 10-4 M) was metabolized by each of the preparations over a 4-h incubation period at rates ranging from 175.8 to 9.2 pmol/106 cells per min with the rates from hepatoctes from: rat > rabbit .mchgt. squirrel monkey > dog. The metabolite profiles determined in extracts of hepatocyte suspensions after 4 h of incubation showed marked species differences. The major metabolite for the rat and squirrel monkey was 1-butyl-3-p-hydroxymethylphenylsulfonylurea (73.2 and 46.7% of total metabolites, respectively). p-Tolylsulfonylurea and p-tolylsulfonamide were the major metabolites found in the dog (44.1 and 40.2%, respectively). Rabbit hepatocytes formed mostly 1-butyl-3-p-carboxyphenylsulfonylurea (63.9%). Both the relative rates of metabolism and the metabolite profiles from hepatocytes from the rat, rabbit and dog correlated well with published in vivo data on TB plasma half-lives and urinary metabolite profiles. Isolated hepatocytes may have utility as in vitro models for comparative in vivo metabolism.