A B S T R A C T The cyclotron-produced radionuclide, 13N, was used to label ammonia and to study its metabolism in a group of 5 normal subjects and 17 patients with liver disease, including 5 with portacaval shunts and 11 with encephalopathy. Arterial ammonia levels were 52-264 ,AM. The rate of ammonia clearance from the vascular compartment (metabolism) was a linear function of its arterial concentration: Amol/min = 4.71 [NH3Ia + 3.76, r = +0.85, P < 0.005. Quantitative body scans showed that 7.4+±0.3% of the isotope was metabolized by the brain. The brain ammonia utilization rate, calculated from brain and blood activities, was a function of the arterial ammonia concentration: ,umol/ min per whole brain = 0.375 [NH3]a -3.6, r = +0.93, P < 0.005. Assuming that cerebral blood flow and brain weights were normal, 47 + 3% of the ammonia was extracted from arterial blood during a single pass through the normal brains. Ammonia uptake was greatest in gray matter. The ammonia utilization reaction(s) appears to take place in a compartment, perhaps in astrocytes, that includes <20% of all brain ammonia. In the 11 nonencephalopathic subjects the [NH3Ia was 100±8 ,uM and the brain ammonia utilization rate was 32±3 ,umol/min per whole brain; in the 11 encephalopathic subjects these were respectively elevated to 149±18 AM (P < 0.01), and 53 ± 7 ,umol/min per whole brain (P <0.01). In normal subjects, -50% of the arterial ammonia was metabolized by skeletal muscle. In patients with portal-systemic shunting, muscle may become the most important organ for ammonia detoxification.