title: Depletion of hepatic UDP-glucuronic acid by drugs that are glucuronidated.
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, 0.5, 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.
authors.forename: S R
authors.initials: SR
authors.lastname: Howell
authors.forename: G A
authors.initials: GA
authors.lastname: Hazelton
authors.forename: C D
authors.initials: CD
authors.lastname: Klaassen
mesh_terms: D000818:Animals; D002701:Chloramphenicol / Q000494:pharmacology; D002995:Clofibric Acid / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005965:Glucuronates / Q000378:metabolism*; D008099:Liver / Q000032:analysis / Q000187:drug effects / Q000378:metabolism*; D008112:Liver Glycogen / Q000032:analysis; D008297:Male; D051379:Mice; D012457:Salicylamides / Q000494:pharmacology; D013997:Time Factors; D014532:Uridine Diphosphate Glucose / Q000032:analysis; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism*; D014539:Uridine Diphosphate Sugars / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D005965:Glucuronates; D008112:Liver Glycogen; D012457:Salicylamides; D014539:Uridine Diphosphate Sugars; D014535:Uridine Diphosphate Glucuronic Acid; D002995:Clofibric Acid; D014635:Valproic Acid; D002701:Chloramphenicol; C031060:salicylamide; D014532:Uridine Diphosphate Glucose