1. The drug phenyl ethyl biguanide (PEBG) was used in vivo and in vitro to study further the relationship between renal gluconeogenesis and ammonia production in the rat.
2. When PEBG was injected intraperitoneally into the rats, it caused a decrease in urinary ammonia in spite of a greater degree of systemic acidosis. PEBG injections also blocked the increase in glucose and ammonia production by renal cortical slices from rats which had been made acidotic by oral administration of ammonium chloride 2 h previously.
3. With increasing concentrations of PEBG in vitro, there was inhibition of gluconeogenesis and ammonia production from glutamine and glutamate as substrates. The two processes were equally inhibited when glutamate was used as substrate but with glutamine, gluconeogenesis was more inhibited than ammonia production.
4. The inhibition of renal gluconeogenesis by PEBG in vitro was similar when succinate, oxaloacetate, fructose, glutamine and glutamate were used as substrates.
5. The results show that PEBG does not inhibit gluconeogenesis by blocking a specific site in the gluconeogenic pathway. In addition, further proof is provided of the physiological interrelationship of renal ammonia production and gluconeogenesis.