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 30 min after the treatment but not after 15 h. 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.