Abstract

The applicability of a pharmacokinetic model for drug interactions by enzyme induction was tested by chronic dosing situation using carbamazepine (Tegretol) as the inducer and clonazepam (Clonopin) as the drug affected. Seven healthy subjects received one 1.0 mg clonazepam tablet once a day for 29 days and one 200 mg carbamazepine tablet once a day from days 8 to 29. Plasma levels of clonazepam were measured by electron-capture gas-liquid chromatography and those of carbamazepine and its epoxide metabolite by gas chromatographic-chemical ionization-mass spectrometry. Clonazepam plasma levels reached an initial steady-state by day 7 and declined to a lower steady-state over 5 to 15 days after additions of carbamazepine. The decrease in clonazepam levels ranged between 19% and 37%. Autoinduction of carbamazepine metabolism was also evident. Urinary excretion of D-glucaric acid increased 2- to 4-fold following carbamazepine administration (p less than 0.005). This increase provided additional evidence that the present interaction was due to enzyme induction. Experimental clonazepam levels were fitted to an induction pharmacokinetic model for multiple dosing with an exponentially increasing clearance. Induced half-lives of clonazepam (mean = 22.5 +/- 11.5 hr) were shorter (p less than 0.005) than control values (32.1 +/- 16.6 hr). Apparent enzyme(s) turnover half-lives ranged between 1 and 6 days.