Pharmacokinetics of Pyrazinoyl-guanidine, 3-Aminopyrazinoyl-guanidine and Their Corresponding Pyrazinoic Acid Metabolites in Humans and Dogs

Abstract

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.

Studies on Pyrazinoylguanidine

“…The doses of PZG (900 mg) and PZA (300 mg) were selected to give comparable blood concentrations based on our previous pharmacokinetic studies [1].…”

“…Pyrazinoylguanidine (PZG), a novel drug structurally related to amiloride, is rapidly hydrolyzed by esterases in human serum to pyrazinoic acid (PZA) [1]. Pharmacokinetic studies in normal human subjects revealed serum half-lives of 1.1 h for PZG and 3.3 h for PZA [1].…”

“…Pharmacokinetic studies in normal human subjects revealed serum half-lives of 1.1 h for PZG and 3.3 h for PZA [1]. PZG has previously been administered for 3 and also 21 days to patients with renal disease because it increases renal clearance of urea [2][3][4][5] and also to hypertensive patients with type II diabetes mellitus because it not only reduces elevated blood pressure, but also down-regulates the glucose-fatty acid cycle [6,7].…”

Studies on Pyrazinoylguanidine

“…STZ-diabetic rats differ in some respects from both NIDDM and insulin-dependent diabetes mellitus, but resemble the latter more than the former [12], The current stud ies had the following objectives: (a) to deter mine whether PZG, glyburide, and metfor min can ameliorate the metabolic abnormali ties of elevated plasma glucose and lipid con centrations in STZ-diabetic rats; (b) to deter mine whether PZG's metabolic effects in STZ-diabetic rats are mediated in part by pyrazinoic acid (PZA), a metabolite of PZG [13]; and (c)to determine whether 3-amino-PZG, a structural analog of PZG [6,7,13], and its hydrolytic product, 3-amino-PZA [6,7,13], can reduce elevated plasma glucose and lipid concentrations that occur in the STZ-diabetic rat model.…”