Altered acetaminophen disposition in fed and food-deprived rats after acute ethanol administration.
The effects of acute ethanol administration and resulting redox changes on the hepatic glucuronidation of acetaminophen were studied in male rats, either fed or deprived of food for 24-72 hr. Regardless of the animal's nutritional status, one of the primary effects of acute ethanol administration in vivo is an increase in hepatic NADH production, usually resulting in an increased intracellular NADH/NAD ratio. Inasmuch as NAD-requiring reactions, such as the conversion of UDP-glucose to UDP-glucuronic acid, could be impaired by such redox changes, the subsequent conjugation of drugs with glucuronic acid may be decreased after ethanol administration. To test this hypothesis, the effects of ethanol on the disposition of acetaminophen (200 mg/kg, ip), a drug excreted primarily as glucuronide and sulfate conjugates in the rat, were studied. In fed rats, administration of 2 g of ethanol per kg produced minimal redox changes, and no significant alterations in hepatic UDP-glucose or UDP-glucuronic acid concentrations. Consequently, no inhibition of acetaminophen-glucuronide formation was observed. However, after at least 24 hr of food deprivation, hepatic UDP-glucuronic acid and acetaminophen-glucuronide concentrations were significantly depressed by ethanol. These results suggest that the effect of ethanol on glucuronide formation in vivo depends on the nutritional state of the animal. In fed rats, homeostatic mechanisms act to prevent any redox-mediated alterations in glucuronide conjugation. However, in food-deprived animals, such compensatory mechanisms are apparently no longer operative, and acetaminophen glucuronidation is inhibited by ethanol administration.
D000082:Acetaminophen / Q000378:metabolism*; D000818:Animals; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D005508:Food Deprivation; D005965:Glucuronates / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D014532:Uridine Diphosphate Glucose / Q000378:metabolism; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
D005965:Glucuronates; D009243:NAD; D014535:Uridine Diphosphate Glucuronic Acid; D000082:Acetaminophen; D000431:Ethanol; D014532:Uridine Diphosphate Glucose