Depletion of hepatic UDP-glucuronic acid by drugs that are glucuronidated.

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, 0.5, 0.75 and 4.0 mmol/kg, respectively. Hepatic UDP-glucuronic acid was decreased by 90% by valproic acid, 91% by chloramphenicol, 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 after drug administration. Salicylamide also was used as a model compound to study the effect of drug loading on the hepatic concentrations of UDP-glucose and glycogen, precursors 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.