Ornithine phenylacetate revisited

In patients with liver failure hyperammonemia is associated with the development of hepatic encephalopathy (HE) and immune impairment. Treatment of hyperammonemia is an unmet clinical need. Ornithine phenylacetate (OP) is a novel drug that is targeted at reducing ammonia concentration in patients with liver disease and therefore a potential treatment for HE. This review describes the mechanism of action of OP and its effect on plasma ammonia levels, brain function and inflammation of OP in both acute and chronic liver failure. Ammonia levels could shown to be reduced for up to 24 h in animal models until 120 h in patients with repeated dosing of the drug. Reduction of plasma ammonia levels is due to the stimulation of ammonia removal in the form of glutamine (through glutamine synthetase), the direct excretion of ammonia in the form phenylacetylglutamine and to a normalisation of glutaminase activity in the gut. Administration of OP is associated with a reduction of brain oedema in rats with chronic bile duct ligation and diminution of intracranial hypertension in a pig model of ALF. Studies to date have indicated that it is safe in humans and trials in overt HE are underway to establish OP as a treatment for this major complication of liver disease.