Cimetidine and carbamazepine: a complex drug interaction

Cimetidine has been shown to inhibit the elimination of carbamazepine after a single oral dose. The mechanism of this interaction is thought to be inhibition of carbamazepine metabolism by the hepatic microsomal enzyme system. Because carbamazepine metabolism undergoes autoinduction with chronic administration, it is not known whether or not the clinical significance of this interaction can be predicted from the results of a single-dose study. The purpose of this study was to evaluate the presence of an interaction under steady-state enzyme-induced conditions. Using an open treatment design, carbamazepine, 300 mg b.i.d., was taken by eight healthy volunteers for 42 days (days 1-42). Cimetidine, 400 mg t.i.d., was taken for 7 days (days 29-35). Steady-state carbamazepine increased 17% after 2 days of cimetidine treatment (from 4.7 +/- 0.8 to 5.5 +/- 1.4 micrograms/ml; p less than 0.05). Six of the eight subjects noted side effects shortly after starting cimetidine treatment. Carbamazepine returned to the pre-cimetidine level and the side effects diminished by the 7th day of cimetidine administration. Therefore, the clinical significance of this interaction appears to be time dependent, and could not be predicted from the results of single-dose studies.