Isobolographic Assessment of the Convulsant Interaction between Theophylline and Caffeine or Pentylenetetrazol in Rats

Abstract

To characterize the convulsant interaction between theophylline and caffeine, male Sprague‐Dawley rats received an iv infusion of one of seven different combinations of these drugs and of each drug individually until the onset of maximal seizures (which occurred within 30 to 40min after the start of the infusion). The total infused doses of the two drugs and their respective concentrations in the serum, brain, and cerebrospinal fluid (CSF) were used for isobolographic analysis. The results are consistent with classical dose‐ and concentration‐addition and do not suggest either antagonism or synergism. The potency ratio based on the doses or serum concentrations was appreciably different from that based on brain or CSF concentrations. The brain:serum and CSF:serum concentration ratios of caffeine were appreciably higher than those of theophylline. Similar experiments were performed with seven combinations of theophylline and pentylenetetrazol (PTZ) and with each of these drugs individually. This second set of experiments also yielded essentially linear isobolographs indicative of dose‐ and concentration‐addition. The potency ratio based on CSF concentrations was appreciably different from ratio values based on doses, and from those based on brain or serum concentrations. These results illustrate a useful strategy for the characterization of pharmacodynamic drug interactions and highlight the importance of the choice of sampling site for determinations of the potency of drug.