The disposition of 2-cyano-1-methyl 3-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)phenyl)guanidine in animals.
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.
Walker
D G
DG
Department of Drug Metabolism, Smith Kline and French Research Ltd., Welwyn, Hertsfordshire, U.K.
Hutchison
M
M
Shepard
T A
TA
Osborne
P M
PM
Allenby
S M
SM
Webb
A J
AJ
Viney
N J
NJ
Pue
M A
MA
Chenery
R J
RJ
Wood
P J
PJ
D000818:Animals; D001345:Autoradiography; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D006146:Guanidines / Q000378:metabolism / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D011485:Protein Binding; D011724:Pyridazines / Q000378:metabolism / Q000493:pharmacokinetics*; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013237:Stereoisomerism; D014018:Tissue Distribution; D014665:Vasodilator Agents / Q000378:metabolism / Q000493:pharmacokinetics*
D006146:Guanidines; D011724:Pyridazines; D014665:Vasodilator Agents; C056215:siguazodan; D003577:Cytochrome P-450 Enzyme System