Ranitidine does not alter single-dose carbamazepine pharmacokinetics in healthy adults

In our recent study, oral cimetidine increased carbamazepine plasma levels after a single oral dose by 26 percent and prolonged the elimination half-life by 18 percent. This effect of cimetidine on carbamazepine could have resulted from enhanced carbamazepine absorption and/or inhibited metabolism. To gain an insight into which mechanism was responsible, we repeated the study with ranitidine, which has nearly identical gastrointestinal effects as cimetidine, but does not inhibit oxidative metabolism. Eight healthy subjects received a single dose of carbamazepine 600 mg po on two occasions separated by one month. In a randomized sequence, they also received ranitidine 300 mg/d or matching placebo starting two days before and continuing until seven days after the carbamazepine dose. Ranitidine did not change the carbamazepine area under the plasma concentration-time curve (324.2 +/- 71.1 micrograms h/ml, placebo vs. 326.3 +/- 65.0 micrograms h/ml, ranitidine; p = 0.84) or the elimination half-life (32.2 +/- 6.4 h, placebo vs. 31.7 +/- 6.1 h, ranitidine; p = 0.62). Since ranitidine does not alter the pharmacokinetic profile of oral carbamazepine, it is unlikely that the changes observed with cimetidine were due to increased carbamazepine absorption. Therefore, the mechanism of the single-dose carbamazepine-cimetidine interaction is probably metabolic inhibition, although the exact pathway (or pathways) affected has not been identified.