Pyrazinoylguanidine (PZG), 3-aminopyrazinoylguanidine (NH₂PZG) and their pyrazinoic acid metabolites were measured by a new reverse-phase HPLC method in the serum of dogs and humans after administration of PZG, NH₂PZG or 2-pyrazinoic acid (PZA). Kinetic properties of PZG and its principal metabolite, PZA, were studied in normal humans and also in azotemic patients, since PZG acts on renal tubules of patients with kidney failure to increase urea elimination. In humans and dogs, PZG was rapidly hydrolyzed to PZA. The serum half-life (t_½) of PZG was 1 h. In turn, PZA was metabolized to 5-hydroxy-PZA, but no evidence appeared for conjugation of PZA with glycine. The apparent volume of distribution of PZG and its 3-amino analog, NH₂PZG, exceeded that of total body water. In the dog the serum t_½ for NH₂PZG was twice that of PZG. Compared to PZG, NH₂PZG and its metabolite, 3-aminopyrazinoic acid, were much stabler in vitro in serum and water.

In streptozotocin (STZ)-induced diabetic rats, pyrazinoylguanidine (PZG) markedly reduced elevated fasting concentrations of plasma glucose, triglycerides, and cholesterol. In contrast, these parameters were unaffected by a sulfonylurea, glyburide, or by a biguanide, metformin. PZG’s glucose- and lipid-lowering effects were dose-dependent. These metabolic effects were also investigated after: (a) pyrazinoic acid (PZA), a metabolite of PZG; (b) 3-amino-PZG, an analog of PZG, and (c) 3-amino-PZA, a hydrolytic product of 3-amino-PZG. PZA moderately reduced elevated fasting glucose and lipid concentrations in STZ-diabetic rats, suggesting partial mediation of PZG’s antidiabetic actions by PZA. Neither 3-amino-PZG nor 3-amino-PZA exerted any glucose- or lipid-lowering effect in STZ-diabetic rats.