Abstract
The aim of this study was to evaluate the potential interaction of aprindine and verapamil in the intestinal mucosa. We examined the effects of verapamil on the plasma concentration of aprindine in patients, on the in vitro metabolism of aprindine using cytochrome P450 3A4 human recombinant microsomes and on aprindine metabolism in the gut wall of the beagle dog.
In the clinical studies, verapamil induced a significant increase in the mean plasma concentration of aprindine (p<0.05). The in vitro studies demonstrated that verapamil inhibited metabolism of aprindine through the inhibition of CYP3A4 in a competitive, concentration-dependent manner. In the animal experiments, the administration of verapamil was associated with a 2.2 fold increase in oral bioavailability of aprindine from 33.64 ± 15.22% to 74.05 ± 5.76%. The increased bioavailability could be attributed to an increase of prehepatic bioavailability from 45.53 ± 16.74% to 93.08 ± 9.67% with a minor contribution from increased hepatic bioavailability from 76.00 ± 5.39% to 79.77 ± 3.15%.
These results demonstrate the existence of a route-specific differental effects verapamil on the plasma concentration and oral bioavailability of aprindine. The increased bioavailability and the increased plasma concentration of aprindine is most likely due to the inhibition of gastrointestinal CYP3A4 enzymes. Aprindine is frequently administered in combination with verapamil. Aprindine has a narrow therapeutic range and displays non-linear kinetics, therefore the effects of verapamil on ap.rindine metabolism may be of clinical significance.
