INDUCTION EFFECT OF PHENOBARBITAL ON THE CARBAMAZEPINE TO CARBAMAZEPINE-10,11-EPOXIDE PATHWAY IN RHESUS-MONKEYS

Abstract

The induction effect of phenobarbital on the carbamazepine to carbamazepine-10,11-epoxide pathway was investigated in 7 rhesus monkeys. Each animal received an 8-h infusion of carbamazepine [an anticonvulsant] on days 1, 5 and 15. In addition, animals received an acute dose (130 mg) of phenobarbital on day 5 followed by 10 daily maintenance doses (40 mg). Plasma samples were assayed for phenobarbital, carbamazepine and epoxide by gas chromatography interfaced with a mass spectrometer in chemical ionization mode. The control mean .+-. SD values of plasma clearance, volume of distribution and t1/2 [half-life] for carbamazepine were 7.3 .+-. 2.37 l/h, 9.61 .+-. 2.29 l and 0.96 .+-. 0.02 h, respectively. The control steady-state ratio of epoxide to carbamazepine was 0.065 .+-. 0.023. An acute loading dose of phenobarbital caused an apparent decrease in clearance (6.05 .+-. 1.80 l/h, P = 0.06) with no apparent changes in other parameters. Subchronic administration of phenobarbital resulted in increases in clearance (14.42 .+-. 4.91 l/h, P = 0.006) and volume of distribution (12.00 .+-. 2.06 l, P = 0.01), a decrease in t1/2 (0.62 .+-. 0.15 h, P = 0.006) and an apparent increase in the epoxide to carbamazepine steady-state ratio (0.085 .+-. 0.013, P = 0.06). The increase in the epoxide to carbamazepine ratio after subchronic administration of phenobarbital suggests that phenobarbital induces the formation of epoxide more than its elimination. This is in direct contrast to the lowering of the epoxide to carbamazepine ratio by carbamazepine autoinduction.