Pharmacokinetics of some homologous series of barbiturates in the intact rat and in the isolated perfused rat liver

TD Yih and JM van Rossum

The pharmacokinetics of a number of 5,5-dialkyl-substituted barbiturates was studied both in the intact rat and in the isolated perfused rat liver. The half-life or the clearance of a reference compound was used as parameter for the drug metabolic activity of the animal and perfused liver. The rate of elimination of the barbiturates was structure-dependent and seemed to be correlated with the lipophilicity of the compounds which was expressed as the octanol-water and hepatocytes-water partition coefficient. Three features could be distinguished. Firstly, there was a decrease in half-life with the introduction of a larger alkyl side chain. Secondly, substitution of a bromoallyl instead of an allyl group had the same effect and thirdly, a more rapidly eliminated barbiturate could be obtained by the introduction of a methyl group onto the nitrogen of the barbiturate nucleus. The elimination clearance constants relative to the heptabarbital clearance were in the same order of magnitude as those found in man. This result suggests that it is possible to predict the clearance values in man by studying relative values in rats.

Volume 203, Issue 1, pp. 184-192, 10/01/1977
Copyright © 1977 by American Society for Pharmacology and Experimental Therapeutics