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 (t½) 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 t½ 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.
Three highly reproducible experiments on drug interaction in normal human volunteers provided anomalous results: chronic halofenate administration shortened plasma antipyrine and bishydroxycoumarin half-lives but prolonged plasma warfarin half-lives. This dissociation in the effect produced by a chronically administered drug on the metabolism of test drugs has not previously been reported in man. Chronic halofenate administration to rats, mice and dogs stimulated several hepatic microsomal drug-metabolizing systems, including those responsible for bishydroxycoumarin and warfarin hydroxylation.
Investigations of effects exerted by various compounds on hepatic microsomal mixed function oxidases are frequently designed for and performed under a single set of conditions with respect to dosage and time of sacrifice after drug administration. From these data a generalization may be derived as to whether a particular drug inhibits, induces or produces no change in these enzymes. Limitations of this approach are illustrated by experiments with GPA 1851, an imidazolone derivative with anti-inflammatory properties. Two hours after a single oral dose of 50 mg/kg, rat hepatic microsomal aniline hydroxylase and ethylmorphine N-demethylase activities were markedly reduced, whereas if the rats were sacrificed 24 h after this oral dose, aniline hydroxylase activity and cytochrome P-450 were enhanced. When rats were sacrificed 24 h after the last of 4 daily oral doses of GPA 1851, no significant change occurred in aniline hydroxylase or ethylmorphine N-demethylase activities, but cytochrome P-450 content was elevated.
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