Urea is the principal nitrogenous waste product of metabolism and is generated from protein breakdown. It is eliminated from the body almost exclusively by the kidneys in urine.

In a series of five enzymatically controlled reactions, known collectively as the “urea cycle”, toxic ammonia resulting from protein breakdown is converted to non-toxic urea.

In addition to ammonia and the five ”urea cycle” enzymes, endogenous production of urea requires the presence of bicarbonate, aspartate and energy input in the form of adenosine triphosphate (ATP).

Carbon dioxide (CO2) is a secondary product of the urea cycle. Almost all of this urea production occurs in the cells of the liver (hepatocytes); the only other source is the cells of the kidneys.

As might be expected, the rate of urea production is influenced by protein content of diet; low-protein diet is associated with reduced urea production and high-protein diet is associated with increased urea production.

Starvation is, perhaps counterintuitively, associated with increased urea production but this is explained by the increased protein released from muscle tissue breakdown (autolysis) that occurs during starvation to provide an energy source.

A small amount (<10 %) of urea is eliminated via sweat and the gut, but most of the urea produced in the liver is transported in blood to the kidneys where it is eliminated from the body in urine.