Noncompetitive-like inhibition of ethanol elimination by cyanamide treatment: pharmacokinetic study.
The effect of acetaldehyde accumulation of ethanol elimination is of interest in medico-legal practice in Japan. We examined the pharmacokinetic mechanism of the inhibition of ethanol metabolism by cyanamide, an inhibitor of mitochondrial aldehyde dehydrogenase. An ethanol solution (0.25-2.0 g/kg body weight) was injected intravenously into male rabbits with or without administration of cyanamide. Cyanamide was injected intraperitoneally (25 mg/kg body weight) to the cyanamide-treated group 2 hr before ethanol injection. Blood ethanol and acetaldehyde concentrations were measured periodically by head-space gas chromatography. The MULTI(RUNGE) computer program was applied for the pharmacokinetic analysis. One- or two-compartment open models with Michaelis-Menten elimination kinetics were used for simultaneous multi-line fitting. The ethanol elimination rate decreased by cyanamide treatment. The border-point concentration between pseudolinear and curvilinear phases was not affected by cyanamide treatment. The estimated Vmax value decreased by cyanamide treatment, whereas the K(m) value did not change. Our results correspond to a noncompetitive-like inhibition of ethanol metabolism. K(m) is related to the border point between pseudolinear and curvilinear phases. Thus, our findings in the blood ethanol concentration-time curve suggest adequate curve-fitting. The product, or competitive, inhibition of alcohol dehydrogenase by acetaldehyde had been reported in enzymological study. The pharmacokinetic manner of inhibition in vivo was different from the enzymologic mechanism in vitro. Other metabolic factors related to ethanol metabolism are thought to be more important than acetaldehyde accumulation itself.
Fujimiya
T
T
Department of Legal Medicine, Kyoto Prefectural University of Medicine, Japan.
Li
Y J
YJ
Uemura
K
K
Ohbora
Y
Y
Komura
S
S
D000079:Acetaldehyde / Q000493:pharmacokinetics; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D003484:Cyanamide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D011817:Rabbits
D000431:Ethanol; D003484:Cyanamide; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde