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Pharmacokinetic Description of Drug Interactions by Enzyme Induction: Carbamazepine-Clonazepam in Monkeys

1979; Elsevier BV; Volume: 68; Issue: 4 Linguagem: Inglês

10.1002/jps.2600680406

1520-6017

Allen A. Lai, René H. Levy,

Epilepsy research and treatment

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 1 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.