ABSTRACT
2-Cyano-1-methyl 3-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)phenyl)guan idine (SK&F 94836), a new positive inotrope/vasodilator, is being evaluated for the treatment of congestive heart failure. The absorption, metabolism, and disposition of the compound have been investigated in the rat, mouse, and dog. SK&F 94836 was rapidly absorbed, widely distributed, and rapidly and completely excreted primarily via the urine. There was no evidence of metabolism of the compound in any of the species studied. The compound showed minimal interaction with cytochrome P-450. The compound contains a chiral center. The enantiomers have been shown not to interconvert in either rat or dog. The serum protein binding was low in all species, including humans, and exhibited no stereoselectivity. Studies conducted in rat and dog using constant rate co-infusion of racemic SK&F 94836 and radiolabeled inulin have demonstrated that SK&F 94836 is eliminated by active tubular secretion.
Subject(s)
Guanidines/pharmacokinetics , Pyridazines/pharmacokinetics , Vasodilator Agents/pharmacokinetics , Animals , Autoradiography , Bile/metabolism , Chromatography, High Pressure Liquid , Cytochrome P-450 Enzyme System/metabolism , Feces/chemistry , Guanidines/metabolism , Intestinal Absorption , Kidney/metabolism , Male , Mice , Protein Binding , Pyridazines/metabolism , Radioimmunoassay , Rats , Rats, Inbred Strains , Species Specificity , Stereoisomerism , Tissue Distribution , Vasodilator Agents/metabolismABSTRACT
1. The metabolism and disposition of 14C-acetamidophenyl pyrazinone has been studied in rat, dog and cynomolgus monkey. The compound was well absorbed and rapidly excreted in urine and faeces by all three species. 2. Distribution of 14C-pyrazinone was rapid and extensive with the exception of the central nervous system where concentrations were at, or below, the limit of detection. 3. Whereas, in in vitro studies, metabolites (but not the parent compound) weakly inhibited some activities of the cytochrome P-450 system, there was evidence from in vivo studies in the rat that the compound and/or its metabolite(s) are weak selective inducers of cytochrome P-450. 4. Metabolite patterns were similar in all three species. The major route of metabolism was glucuronidation at the oxygen of the pyrazinone ring. Other metabolites originated from metabolism by gut microflora with subsequent hepatic metabolism.