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Journal of Pharmacology And Experimental Therapeutics, Vol. 152, Issue 3, 363-371, 1966
Copyright © 1966 by American Society for Pharmacology and Experimental Therapeutics

TIME COURSE DIFFERENCES IN THE METABOLISM OF DRUGS BY HEPATIC MICROSOMES FROM RATS, RABBITS AND MICE

Theodore E. Gram 1 and James R. Fouts 1

1 Department of Pharmacology, College of Medicine, State University of lowa, Iowa City, Iowa

In vitro time course studies of the metabolism of hexobarbital, codeine, zoxazolamine, p-nitrobenzoic acid, Neoprontosil, aminopyrine and benzpyrene have been carried out by employing hopatic microsomes from rabbits, rats and mice. In general, relatively early deviation from linear metabolism was observed with rat liver microsomes; with some substrates, this occurred in less than 15 min. In several rat liver, early plateaus in drug metabolic activity occurred, with no further metabolism of drug beyond 45 or 60 min of incubation. By contrast, rabbit and mouse liver microsome metabolized drugs linearly with time for considerably longer periods, 60 to 90 min in some cases. The early departure from linearity seen with rat liver microsomes was not influenced by doubling substrate concentrations, doubling cofactor concentrations or addition of excess reduced nicotinamide adenine dinucleotide phosphate. Similarly, it did not seem to be the result of product inhibition or of inactivation of cytochrome P-450. The period of linear drug metabolism in rats and rabbits was not influenced by phenobarbital-induced microsomal enzyme stimulation, thus indicating that the same factor were operative in the control and stimulated preparations. Preincubation of rat and rabbit liver microsomes for 60 min resulted in a marked diminution in the enzymatic activity of the rat preparation, but had much less, if any, effect on the activity of rabbit liver microsomes. Incubation of washed rat liver microsomes in hypotonic media led to rapid swelling and lysis of the vesicles which would result, presumably, in enzyme inactivation. Under similar conditions, rabbit liver microsomes displayed only slight changes. The available data support the view that the drug-metabolizing enzymes in rat liver microsomes are more subject to inactivation than those of the rabbit.

Accepted on January 6, 1966




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Copyright © 1966 by the American Society for Pharmacology and Experimental Therapeutics.