Parallel first-order and Michaelis-Menten elimination kinetics of ethanol. Respective role of alcohol dehydrogenase (ADH), non-ADH and first-order pathways

Abstract

Elimination kinetics of ethanol without (control group) and with pyrazole [alcohol dehydrogenase (ADH) inhibitor] pretreatment was studied with changing the i.v. dose amount to evaluate the respective role of ADH and non-ADH pathways in a rabbit. The moment analysis of the blood ethanol concentration-time curves showed that the normalized area under the blood ethanol concentration-time curve and the first moment increase with increasing dose amount in the control and pyrazole-pretreated groups. These increases suggested the capacity-limited elimination of ethanol through pyrazole-insensitive non-ADH pathways as well as through ADH pathway as pyrazole would fully block the oxidation of ethanol through ADH pathway. The simultaneous multiline fitting using time curves after five different doses also was attempted to determine the pharmacokinetic model by the application of minimum Akaike's information criterion estimation. Akaike's information criterion, consequently, showed the minimum for a two-compartment model with parallel first-order and Michaelis-Menten elimination kinetics. The computer analysis using this model yielded almost the same values of the volume of distribution and of the first-order elimination rate constant between both groups. The distribution of ethanol and the first-order elimination process were not influenced by pyrazole treatment. Km (0.57 mg/ml) of the pyrazole-pretreated group was higher than Km (0.03 mg/ml) of the control group. These results suggest that ADH pathway is readily saturated and non-ADH pathways are unsaturated over the wide range of concentration. The first-order process as well as non-ADH pathways are concluded to occupy the considerable part in the ethanol elimination at higher blood concentration.