Dose-dependent pharmacokinetics of the antihypertensive 2,3,4,4a-tetrahydro-1H-pyrazino[1,2a]quinoxalin-5-(6H)-one in dogs and rats.
A sensitive and reproducible GLC assay was developed for determining 2,3,4,4a-tetrahydro-1H-pyrazino[1,2a]quinoxalin-5(6H)-one (I) in biological fluids, utilizing the electron-capturing capability of the heptafluorobutyryl derivative. After single 2.5- and 10-mg/kg oral and intravenous doses to three dogs, plasma concentration-time data for I were fitted to a biexponential equation and pharmacokinetic parameters were calculated. A dose-dependency for certain parameters, most notably total body clearance (ClT), was indicated. The difference in ClT for the low and high dose was statistically significant. After single 5-, 25-, and 50-mg/kg intragastric doses were given to rats, the decline in plasma concentrations of I with time followed a monoexponential equation. As with dogs, there was a disproportionate change in kinetic parameters with increasing dose for rats. While simple Michaelis-Menten kinetics were not evident, nonlinearity in biotransformation (intrinsic clearance) appeared to be the cause for the dose-dependent pharmacokinetics.
D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism*; D004285:Dogs; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D011810:Quinoxalines / Q000378:metabolism*; D051381:Rats; D013045:Species Specificity
D000959:Antihypertensive Agents; D011810:Quinoxalines; C034450:2,3,4,4a-tetrahydro-1H-pyrazino(1,2a)quinoxalin-5-(6H)one