EFFECT OF LIPID-FREE TOTAL PARENTERAL-NUTRITION ON HEPATIC DRUG CONJUGATION IN RATS

The effect of total parenteral nutrition (TPN) on drug conjugation in male Sprague-Dawley rats was examined using a nutrition solution compo sed of amino acids and glucose. The overall disposition of acetaminoph en including the formation kinetics of the sulfate and glucuronide met abolites was used as an in vivo probe. Selected drug metabolizing enzy me activities also were examined in vitro. TPN, 200 kcal/kg/day, was a dministered by continuous i.v. infusion for 14 days and changes elicit ed were compared to control animals allowed free access to rat chow. T PN decreased the total clearance of acetaminophen by 34% and the forma tion clearance to acetaminophen sulfate by 47%. The formation clearanc e of acetaminophen to acetaminophen glucuronide was unaffected by TPN. Cytochrome P450 concentration and oxidative demethylase activity towa rd p-nitroanisole were decreased in parallel, 47 and 53%, respectively , and UDP-glucuronosyltransferase activity with p-nitrophenol and acet aminophen as the acceptor aglycones was decreased 44 and 25%, respecti vely in the animals receiving TPN. Sulfotransferase activity toward bo th p-nitrophenol and acetaminophen decreased 28% in animals receiving TPN vs. ad libitum rat chow. Administration of the parenteral nutritio n solution as a continuous enteral infusion via a doudenal catheter sl ightly decreased p-nitroanisole demethylase activity (26%), but had no other significant effects on either cytochrome P450 concentration or on drug conjugating enzyme activities determined in vitro. These resul ts show that parenteral nutrition administered i.v. depresses drug con jugation and suggest that alterations in both hepatic oxidative and co njugative biotransformation arising from total parenteral nutrition ar e largely attributable to bypassing the intestinal route for nutrient intake.