L-ornithine and phenylacetate synergistically produce sustained reduction in ammonia and brain water in cirrhotic rats.
Treatment of hyperammonemia and hepatic encephalopathy in cirrhosis is an unmet clinical need. The aims of this study were to determine whether L-ornithine and phenylacetate/phenylbutyrate (administered as the pro-drug phenylbutyrate) (OP) combined are synergistic and produce sustained reduction in ammonia by L-ornithine acting as a substrate for glutamine synthesis, thereby detoxifying ammonia, and the phenylacetate excreting the ornithine-derived glutamine as phenylacetylglutamine in the urine. Sprague-Dawley rats were studied 4 weeks after bile duct ligation (BDL) or sham operation. Study 1: Three hours before termination, an internal carotid sampling catheter was inserted, and intraperitoneal saline (placebo), OP, phenylbutyrate, or L-ornithine were administered after randomization. BDL was associated with significantly higher arterial ammonia and brain water and lower brain myoinositol (P < 0.01, respectively), compared with sham-operated controls, which was significantly improved in the OP-treated animals; arterial ammonia (P < 0.001), brain water (P < 0.05), brain myoinositol (P < 0.001), and urinary phenylacetylglutamine (P < 0.01). Individually, L-ornithine or phenylbutyrate were similar to the BDL group. In study 2, BDL rats were randomized to saline or OP administered intraperitoneally for 6 hours or 3, 5, or 10 days and were sacrificed between 4.5 and 5 weeks. The results showed that the administration of OP was associated with sustained reduction in arterial ammonia (P < 0.01) and brain water (P < 0.01) and markedly increased arterial glutamine (P < 0.01) and urinary excretion of phenylacetylglutamine (P < 0.01) in each of the OP treated groups.


CONCLUSIONS
The results of this study provide proof of the concept that L-ornithine and phenylbutyrate/phenylacetate act synergistically to produce sustained improvement in arterial ammonia, its brain metabolism, and brain water in cirrhotic rats.
Liver Failure Group, Institute of Hepatology, University College London, UK.
Nathan A
NA
Davies
Gavin
G
Wright
Lars M
LM
Ytrebø
Vanessa
V
Stadlbauer
Ole-Martin
OM
Fuskevåg
Claudia
C
Zwingmann
D Ceri
DC
Davies
Abeba
A
Habtesion
Stephen J
SJ
Hodges
Rajiv
R
Jalan
D000641:Ammonia / Q000378:metabolism*; D000818:Animals; D001834:Body Water / Q000187:drug effects* / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D004357:Drug Synergism; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D009952:Ornithine / Q000494:pharmacology*; D010648:Phenylacetates / Q000494:pharmacology*; D010654:Phenylbutyrates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D010648:Phenylacetates; D010654:Phenylbutyrates; D000641:Ammonia; D009952:Ornithine