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 patients who are unable to eat. Long-term parenteral nutrition is accompanied by alterations in gut and liver function including changes in drug metabolism. This study examined the effects of lipid-free total parenteral nutrition in rats on (1) the overall elimination pharmacokinetics of acetaminophen, (2) changes in sulfation and glucuronidation pathways during acetaminophen elimination, and (3) hepatic drug metabolizing enzyme activities determined in vitro.


METHODS
Chronic indwelling catheters were implanted in the aorta, inferior vena cava, and portal 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 pharmacokinetics were characterized in vivo and selected drug metabolizing enzyme activities were determined in vitro.


RESULTS
Parenteral nutrition 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 decreased the formation clearance to acetaminophen sulfate (from 6.2 +/- 0.4 to 3.9 +/- 0.5 mL/min per kg; p < .05). Parenteral nutrition decreased microsomal cytochrome P450 concentration (47%), p-nitroanisole demethylase activity (68%) and p-nitrophenol UDP-glucuronosyltransferase activity (58%). Cytosolic glutathione-S-transferase activity towards 1-chloro-2,4-dinitrobenzene decreased 29%. Sulfotransferase activity towards p-nitrophenol and acetaminophen was decreased 48% and 25%, respectively.


CONCLUSIONS
Lipid-free, total parenteral nutrition depresses drug conjugative metabolism in rats. The magnitude of this effect in humans remains to be investigated.
Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah, Salt Lake City 84112, USA.
R B
RB
Raftogianis
M R
MR
Franklin
R E
RE
Galinsky
D000082:Acetaminophen / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000378:metabolism; D008658:Inactivation, Metabolic; D007262:Infusions, Intravenous; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010289:Parenteral Nutrition, Total / Q000009:adverse effects* / Q000379:methods; D011169:Portal Vein; D051381:Rats; D017207:Rats, Sprague-Dawley
D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System