INTERSPECIES SCALING OF CIMETIDINE THEOPHYLLINE PHARMACOKINETIC INTERACTION - INTERSPECIES SCALING IN PHARMACOKINETIC INTERACTIONS

The aim of the present study was the use of an interspecies scaling ap proach to predict drug interactions during preclinical drug dispositio n studies. Theophylline and cimetidine were selected because of their documented interaction. The literature was searched for pharmacokineti c data of intravenously administered theophylline alone and in the pre sence of cimetidine in humans, dogs and rats. Further, we determined t he theophylline-cimetidine drug interaction in rabbits. Application of allometric equations to the pharmacokinetic parameters and the conver sion of chronological time into pharmacokinetic time allowed us to obt ain the complex Dedrick plot for theophylline when administered alone or in combination with cimetidine. A superimposable kinetic profile wa s obtained for the plasma levels of theophylline in all species studie d, both with and without cimetidine. From the terminal phase of the cu rves it is possible to calculate the elimination half-life: 2.69 apoli sychrons for theophylline when it is administered alone and 3.86 apoli sychrons when it is administered in combination with cimetidine. This 43% increase in t(1/2) is similar to the increase in the elimination h alf-life of theophylline in humans when it is administered after pretr eatment with cimetidine. These results show that an interspecies scali ng approach may be useful to predict the effect of interactions in hum ans from the results obtained in preclinical research with new drugs.