DEPLETION OF HEPATIC UDP-GLUCURONIC ACID BY DRUGS THAT ARE GLUCURONIDATED

  • 1 March 1986
    • journal article
    • research article
    • Vol. 236  (3) , 610-614
Abstract
Salicylamide, clofibric acid, valproic acid and chloramphenicol are all known to be glucuronidated. The effects of these compounds on the hepatic concentration of UDP-glucuronic acid, the cosubstrate for glucuronidation, were studied in mice and found to lower hepatic UDP-glucuronic acid in a dose- and time-dependent fashion. Valproic acid, chloramphenicol, salicylamide and clofibric acid depleted hepatic UDP-glucuronic acid significantly at dosages as low as 0.5, 0.75 and 4.0 mmol/kg, respectively. Hepatic UDP-glucoronic acid was decreased by 90% by valproic acid, 91% by chloramphicol, 98% by salicylamide and 41% by clofibric acid (after dosages of 4,2, 1 and 5 mmol/kg, respectively). UDP-glucuronic acid was depleted maximally by 15 min after drug administration. Salicylamide also was used as a model compound to study the effect of drug loading on the hepatic concentrations of UDP-glucuronic acid. It was found that, in addition to UDP-glucuronic acid, salicylamide (4 mmol/kg) also depleted UDP-glucose and glycogen by about 50%. These data suggest that large drug loads cause an increase flux through the glucuronic acid pathway and that hepatic UDP-glucuronic acid is consumed more rapidly than it is produced.