THE DEPRESSION OF HEPATIC DRUG CONJUGATION REACTIONS IN RATS AFTER LIPID-FREE TOTAL PARENTERAL-NUTRITION ADMINISTERED VIA THE PORTAL-VEIN

Background: Total parenteral nutrition provides nutrition support in p atients who are unable to eat. Long-term parenteral nutrition is accom panied by alterations in gut and liver function including changes in d rug metabolism. This study examined the effects of lipid-free total pa renteral nutrition in rats on (1) the overall elimination pharmacokine tics of acetaminophen, (2) changes in sulfation and glucuronidation pa thways during acetaminophen elimination, and (3) hepatic drug metaboli zing enzyme activities determined in vitro. Methods: Chronic indwellin g catheters were implanted in the aorta, inferior vena cava, and porta l vein of adult male Sprague-Dawley rats. Total parenteral nutrition, consisting of 25% dextrose, 5% amino acids, electrolytes, and vitamins , was infused via the portal vein for up to 14 days. Acetaminophen pha rmacokinetics were characterized in vivo and selected drug metabolizin g enzyme activities were determined in vitro. Results: Parenteral nutr ition for 10 days decreased the total clearance of acetaminophen by 23 % (from 11.5 +/- 1.4 to 8.9 +/- 1.4 mL/min per kg; p < .05) and decrea sed the formation clearance to acetaminophen sulfate (from 6.2 +/- 0.4 to 3.9 +/- 0.5 mL/min per kg; p < .05). Parenteral nutrition decrease d microsomal cytochrome P450 concentration (47%), p-nitroanisole demet hylase activity (68%) and p-nitrophenol UDP-glucuronosyltransferase ac tivity (58%). Cytosolic glutathione-S-transferase activity towards 1-c hloro-2,4-dinitrobenzene decreased 29%. Sulfotransferase activity towa rds P-nitrophenol and acetaminophen was decreased 48% and 25%, respect ively. Conclusion: Lipid-fi-ee, total parenteral nutrition depresses d rug conjugative metabolism in rats. The magnitude of this effect in hu mans remains to be investigated.