Dadsetan, Sherry7; Sørensen, Michael3; Bak, Lasse Kristoffer8; Vilstrup, Hendrik5; Ott, Peter5; Schousboe, Arne8; Jalan, Rajiv6; Keiding, Susanne3; Waagepetersen, Helle S8
1 Department of Drug Design and Pharmacology, Faculty of Pharmaceutical Sciences, Københavns Universitet2 Drug Research Academy B, Drug Research Academy, Faculty of Pharmaceutical Sciences, Københavns Universitet3 Århus Universitets Hospital4 Molecular and Cellular Pharmacology, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet5 Institut for Klinisk Medicin - Medicinsk Afd. V, NBG6 University College London, Medical School, London7 Drug Research Academy B, Drug Research Academy, Faculty of Pharmaceutical Sciences, Københavns Universitet8 Molecular and Cellular Pharmacology, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet
Combined administration of ornithine and phenylacetate (OP) is proposed as a novel treatment of hyperammonemia and hepatic encephalopathy. Ornithine is believed to increase ammonia fixation into glutamine in muscle tissue and glutamine is subsequently thought to react with phenylacetate forming phenylacetylglutamine (PAGN) which is excreted in urine. The aim of the present study was to elucidate the interorgan metabolism of ornithine and ammonia in cirrhotic rats treated with OP in order to obtain an understanding of the underlying mechanisms of the beneficial effect of the treatment, which are largely unknown. Bile duct ligated cirrhotic rats and SHAM rats were treated with OP or saline for five days. [2,5-(15)N]Ornithine or (15)NH(4)(+) were administered intravenously and the incorporation of (15)N in amino acids as well as the content of the amino acids were subsequently determined in plasma, skeletal muscle, liver and kidney. In BDL rats, OP treatment reduced arterial ammonia concentration and increased that of glutamine 30min after the treatment but not after 15h. OP treatment did not increase (15)N labeling in glutamine from [2,5-(15)N]ornithine and (15)NH(4)(+) in skeletal muscle or liver. However, the extent of glutamine labeling from [2,5-(15)N]ornithine or (15)NH(4)(+) was similar in arterial blood and liver and higher than that in skeletal muscle. These findings suggest that the effect of OP was related to hepatic metabolism of ornithine. PAGN could not be detected in urine or blood in any of the rats which may explain why OP treatment only reduced arterial ammonia transiently.
Biochemical Pharmacology, 2013, Vol 85, Issue 1, p. 115-23
Acetates; Ammonia; Animals; Arteries; Bile Ducts; Drug Interactions; Female; Glutamine; Hyperammonemia; Kidney; Ligation; Liver; Liver Cirrhosis, Biliary; Muscle, Skeletal; Nitrogen Isotopes; Ornithine; Phenols; Rats; Rats, Wistar; Tissue Distribution