Evaluation of the excretion, and metabolism of the cardiotonic agent bemoradan in male rats and female beagle dogs.
The excretion and metabolism of (+/-) [6-(3,4-dihydro-3-oxo-1,4[2H]-benzoxazine-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one] (bemoradan; RWJ-22867) have been investigated in male Long-Evans rats and female beagle dogs. Radiolabeled [14C] bemoradan was administered to rats as a singkle 1 mg/kg suspension dose while the dogs received 0.1 mg/kg suspension dose. Plasma (0-24 h; rat and dog), urine (0-72 h; rat and dog) and fecal (0-72 h; rat and dog) samples were collected and analyzed. The terminal half-life of the total radioactivity for rats from plasma was estimate to be 4.3 +/- 0.1 h while for dogs it was 7.5 +/- 1.3 h. Recoveries of total radioactivity in urine and feces for rats were 49.1 +/- 2.4% and 51.1 +/- 4.9% of th dose, respectively. Recoveries of total radioactivity in urine and feces for dogs were 56.2 +/- 12.0% and 42.7 V 9.9% of the dose, respectively. Bemoradan and a total of nine metabolites were isolated and tentatively identified in rat and dog plasma, urine, and fecal extracts. Unchanged bemoradan accounted for approimately < 2% of the dose in rat urine and 20% in rat feces. Unchanged bemoradan accounted for approximately 5% of the dose in urine and 16% in feces in dog. Six proposed pathways were used to describe the metabolites found in rats and dogs: pyridazinyl oxidations, methyl hydroxylation, hydration, N-oxidation, dehydration and phase II conjugations.
Wu
W N
WN
Division of Preclinical Development, The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477, USA.
Caldwell
G W
GW
Masucci
J A
JA
Gauthier
A D
AD
D000818:Animals; D048588:Benzoxazines; D002316:Cardiotonic Agents / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008956:Models, Chemical; D010078:Oxazines / Q000493:pharmacokinetics*; D011724:Pyridazines / Q000493:pharmacokinetics*; D051381:Rats; D020318:Rats, Long-Evans
D048588:Benzoxazines; D002316:Cardiotonic Agents; D010078:Oxazines; D011724:Pyridazines; C062457:bemoradan