Effect of galactosamine-induced hepatic UDP-glucuronic acid depletion on acetaminophen elimination in rats. Dispositional differences between hepatically and extrahepatically formed glucuronides of acetaminophen and other chemicals.
Galactosamine (GAL) markedly depletes hepatic UDP-glucuronic acid (UDP-GA) whereas extrahepatic UDP-GA is minimally affected. This suggests that GAL predominantly inhibits hepatic glucuronidation. Therefore, the effect of GAL-induced hepatic UDP-GA depletion was examined in bile duct-cannulated rats to determine the role of hepatic glucuronidation in the disposition of acetaminophen (AA). GAL markedly altered the fate of AA-glucuronide but had little or no effect upon other AA metabolites. GAL decreased the biliary excretion of AA-glucuronide up to 92%, whereas reductions in blood levels and urinary excretion of AA-glucuronide did not exceed 50%. This suggests that AA-glucuronide excreted in bile is predominantly of hepatic origin whereas AA-glucuronide found in blood and urine is derived from both hepatic and extrahepatic tissues. Data in the present and previous studies [Gregus, Watkins, Thompson, Klaassen: J. Pharmacol. Exp. Ther. 225, 256, (1983)] indicate that GAL greatly reduced the biliary excretion of AA- and valproic acid-glucuronide whereas the biliary excretion of the glucuronides of phenolphthalein, iopanoic acid, bilirubin, and diethylstilbestrol was only partially decreased. This difference appears to be largely due to differential contributions by the liver and extrahepatic tissues in the glucuronidation of various compounds as well as the availability of glucuronides formed in extrahepatic tissues for biliary excretion. Specifically, the extrahepatically formed glucuronide conjugates of AA and valproic acid are not readily available for biliary excretion whereas the glucuronides of the other compounds are readily excreted into bile.(ABSTRACT TRUNCATED AT 250 WORDS)
D000082:Acetaminophen / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D001646:Bile / Q000032:analysis; D001659:Biliary Tract / Q000378:metabolism; D005688:Galactosamine / Q000494:pharmacology*; D008099:Liver / Q000032:analysis / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014535:Uridine Diphosphate Glucuronic Acid / Q000032:analysis / Q000172:deficiency* / Q000378:metabolism; D014539:Uridine Diphosphate Sugars / Q000172:deficiency*
D014539:Uridine Diphosphate Sugars; D014535:Uridine Diphosphate Glucuronic Acid; D000082:Acetaminophen; D005688:Galactosamine