L-Ornithine L-Aspartate: Multimodal Therapeutic Agent for Hyperammonemia and Hepatic Encephalopathy in Cirrhosis

Abstract

L-ornithine L-aspartate (LOLA) is a 1:1 stable salt of naturally-occurring amino acids L-ornithine and L-aspartic acid. Following oral administration, LOLA is rapidly absorbed dependent on the Na+ ion gradient. The elimination half-life is estimated to be in the 30–45 min range with bioavailability of 82.2%. LOLA has the proven capacity to cause lowering of blood ammonia and it does so as a result of multiple established mechanisms. Being a urea cycle intermediate and, more specifically, an activator of carbomyl phosphate synthetase, L-ornithine stimulates ammonia removal as urea by periportal hepatocytes. Both L-ornithine and L-aspartate are substrates for transamination reactions resulting in formation of glutamate, the obligate substrate for glutamine synthetase located in perivenous hepatocytes, skeletal muscle and brain. Increases of brain glutamine correlate with severity of Hepatic Encephalopathy (HE) in patients with cirrhosis. In cirrhosis, the normal pattern of inter-organ trafficking is modified and skeletal muscle replaces the liver as the major ammonia-removing organ. Muscle wasting (sarcopenia) occurs in cirrhosis as a result of exposure to ammonia and this seriously limits its ammonia-lowering capacity leading to a vicious cycle and worsening of hyperammonemia. Trials demonstrate that treatment with LOLA improves muscle function in patients with cirrhosis. There is evidence to suggest that LOLA also has direct hepatoprotective actions in these patients via mechanisms related to the production of antioxidants and the synthesis of nitric oxide leading to improved hepatic microcirculation. Over 20 randomized controlled trials together with systematic reviews and meta-analyses have demonstrated that LOLA is effective for the prevention and treatment of HE in cirrhosis where improvements in mental state occurred as a consequence of the lowering of circulating ammonia.