THE KINETICS OF CHLORAL HYDRATE METABOLISM IN MICE AND THE EFFECT THEREON OF ETHANOL

¹ Pharmacology Department, School of Medicine, State University of New York at Buffalo, Buffalo, New York

The kinetics of chloral hydrate metabolism after the i.p. administration of this agent were investigated in mice. Chloral hydrate was found to have a biologic half-life in this species of 12.0 minutes, the rate constant for its disappearance being 0.057 min^-1. Of the administered chloral hydrate 56% was reduced to trichloroethanol, the rate constant for this process being 0.032 min^-1. Trichloroethanol itself was found to be metabolized much more slowly, the rate constant for its disappearance being 0.0033 min^-1 and its biologic half-life in mice 211 minutes. From this data it proved possible to predict quantitatively the degree of accumulation of trichloroethanol in vivo after chloral hydrate administration and to confirm the prediction experimentally. It was observed that in mice trichloroethanol is not oxidized to trichloroacetic acid in any detectable amounts. Trichloroacetic acid formation from chloral hydrate was found to occur with a rate constant of 0.0064 min^-1 resulting in the oxidation in this manner of some 11% of the administered chloral hydrate. About 9.6% of the administered chloral hydrate was found to escape metabolism altogether, at least 4.5% of it by excretion into urine. Co-administration of an equimolar amount of ethanol was found to lead to a significant increase in the rate of chloral hydrate disappearance, the rate constant for it under these conditions being 0.075 min^-1. The rate constant for trichloroacetic acid formation did not change significantly under these circumstances although significantly less trichloroacetic acid was formed from the administered chloral hydrate. Trichloroethanol formation was the only other process whose rate was increased by co-administration of ethanol, the rate constant under these conditions (0.059 min^-1) being increased by 84%. The rate of trichloroethanol disappearance was found not to be significantly altered by ethanol co-administration. On this basis it was possible to quantitatively predict an even greater accumulation of trichloroethanol in vivo and also to confirm this experimentally. It was also found that after i.v. administration trichloroethanol is 1.18 times as potent as chloral hydrate on a molar basis in causing a loss of righting reflexes. it is concluded that the greater accumulation of trichloroethanol which occurs after co-administration of ethanol can adequately explain the observed potentiation by this agent of the effects of chloral hydrate in mice.