PHARMACOKINETIC DESCRIPTION OF DRUG-INTERACTIONS BY ENZYME-INDUCTION - CARBAMAZEPINE-CLONAZEPAM IN MONKEYS

The applicability of a pharmacokinetic model for drug interactions by enzyme induction was tested in rhesus monkeys using a design in which both the inducer (carbamazepine) and the induced agent (clonazepam) were infused chronically. Two types of studies were conducted. Studies I and II examined the kinetic behavior of plasma clonazepam levels during induction and postinduction, respectively. The addition of carbamazepine (Study I) caused the preinduction clonazepam steady‐state level to decrease exponentially to a lower (induced) steady state after lag times of 14.0–60.5 hr, and the removal of carbamazepine (Study II) caused induced clonazepam steady‐state levels to climb exponentially to a higher steady state after lag times of 34.0–81.0 hr. The extent of induction ranged between 23 and 54%. The time course of clonazepam levels was described in terms of a one‐compartment induction model with zero‐order input and a metabolic clearance that increased (Study I) or decreased (Study II) exponentially with time. In both studies, induced clonazepam half‐lives (3.7–7.7 hr) were significantly shorter (p < 0.0005) than control values (5.2–12.2 hr). Apparent enzyme turnover half‐lives were shorter in Study II (2.7–19.3 hr) than in Study I (6.9–66.4 hr). A two‐ to threefold increase in urinary excretion of D‐glucaric acid during carbamazepine administration provided additional evidence that the present interaction was due to enzyme induction. Copyright © 1979 Wiley‐Liss, Inc., A Wiley Company