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 Km value did not change. Our results correspond to a noncompetitive‐like inhibition of ethanol metabolism. Km 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.
The individual differences in alcohol pharmacokinetics were studied using the one-compartment model with first-order absorption and zero-order elimination kinetics in humans. The blood alcohol concentrations (BACs) were simulated by obtained parameters, absorption rate constant (ka), and climination rate constant (β). The 81 healthy young Japanese volunteers, who had been divided into those without alcohol-induced facial flushing (nonflushers) and those with facial flushing (flushers) according to alcohol patch test results and a questionnaire beforehand, ingested 0.50 g/kg ethanol within 1 minute. Breath alcohol concentrations (BrACs) were measured during absorption and during the elimination period. BACs were obtained based on BrACs. Fifteen percent of subjects exhibited low BAC profile (below 0.4 mg/mL) (first-pass effect [FPE] group), although the majority showed normal BAC profile (normal group). The ka was approximately 5 to 8 (h(-1)) in the normal group without significant difference between nonflushers and flushers, whereas that in the FPE group was significantly smaller than in the normal group. For the normal group, peak BACs were well simulated by the one-compartment model with first-order absorption and zero-order elimination kinetics. A considerable portion of subjects exhibited FPE. Absorption of alcohol from the intestine plays an important role in alcohol pharmacokinetics in humans.
Background: Acetaldehyde (AcH) is a toxic metabolite of ethanol (EtOH). The pharmacokinetics of blood AcH during EtOH oxidation was studied with or without the administration of aldehyde dehydrogenase 2 inhibitor (cyanamide) in rabbits.Methods: An bolus of EtOH saline solution (0.25, 0.5, 1.0, 1.5, and 2.0 g/kg) was injected intravenously. Cyanamide was administered intraperitoneally (25 mg/kg body weight) to the cyanamide-treated group. Blood EtOH and AcH concentrations were measured by using head-space gas chromatography.Results: In the control group, the first peak of the blood AcH appeared immediately and the second elevation appeared 1 to 4 hr after administration at a high EtOH dose. The blood AcH levels other than the second elevation part were significantly correlated to the blood EtOH levels. In the cyanamide-treated group, a peak and a plateau formed at the time corresponding to the second peak in the control group. The peak and plateau concentration of AcH increased markedly. We attempted simultaneous curve fitting, using the five blood EtOH and AcH concentration-time curves, to determine the pharmacokinetic model. Consequently, the AcH elimination was best described by a Michaelis-Menten kinetic model in both groups.Conclusions: The blood AcH profile was suggested to consist of the first and second components that are related to the blood EtOH concentration itself and the metabolic formation of AcH, respectively. With higher EtOH doses or aldehyde dehydrogenase 2 inhibition, the second component becomes prominent as a result of the capacity-limited property of the metabolism of AcH, which is described by Michaelis-Menten elimination kinetics.
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