NONCOMPETITIVE-LIKE INHIBITION OF ETHANOL ELIMINATION BY CYANAMIDE TREATMENT - PHARMACOKINETIC STUDY

The effect of acetaldehyde accumulation of ethanol elimination is of i nterest in medico-legal practice in Japan. We examined the pharmacokin etic mechanism of the inhibition of ethanol metabolism by cyanamide, a n inhibitor of mitochondrial aldehyde dehydrogenase. An ethanol soluti on (0.25-2.0 g/kg body weight) was injected intravenously into male ra bbits with or without administration of cyanamide. Cyanamide was injec ted intraperitoneally (25 mg/kg body weight) to the cyanamide-treated group 2 hr before ethanol injection. Blood ethanol and acetaldehyde co ncentrations were measured periodically by head-space gas chromatograp hy. The MULTI(RUNGE) computer program was applied for the pharmacokine tic analysis. One- or two-compartment open models with Michaelis-Mente n elimination kinetics were used for simultaneous multi-line fitting. The ethanol elimination rate decreased by cyanamide treatment. The bor der-point concentration between pseudolinear and curvilinear phases wa s not affected by cyanamide treatment. The estimated V-max value decre ased by cyanamide treatment, whereas the K-m value did not change. Our results correspond to a noncompetitive-like inhibition of ethanol met abolism. K-m is related to the border point between pseudolinear and c urvilinear phases. Thus, our findings in the blood ethanol concentrati on-time curve suggest adequate curve-fitting. The product, or competit ive, inhibition of alcohol dehydrogenase by acetaldehyde had been repo rted in enzymological study. The pharmacokinetic manner of inhibition in vivo was different from the enzymologic mechanism in vitro. Other m etabolic factors related to ethanol metabolism are thought to be more important than acetaldehyde accumulation itself.