The interaction of cimetidine with rat liver microsomes.

The binding of cimetidine to rat liver microsomes in M/15 phosphate buffer, pH 7.9, has been investigated by difference spectroscopy and also by equilibrium partition studies, the latter method providing the more definitive characterization of the interaction in the pharmacologically relevant, low micromolar range of drug concn. In addition, the effect of cimetidine on the rate of dilution-induced displacement of [3H]cimetidine from rat liver microsomes has been used to justify consideration of the binding results in terms of two distinct and independent classes of microsomal site, governed by dissociation constants of 8.3 and 104 microM under the above conditions. By demonstrating unequivocally the existence of the stronger interaction, this investigation has provided an acceptable experimental basis for considering the undesired side effect of cimetidine in concomitant use with a number of other drugs to be the consequence of its inhibition of their monooxygenase-dependent metabolism.