Induction effect of phenobarbital on carbamazepine-10,11-epoxide kinetics in the rhesus monkey

A previous study showed that coadministration of phenobarbital (PB) and carbamazepine (CBZ) to the rhesus monkey resulted in an increase in the steady-state ratio of carbamazepine-10,11-epoxide (EPO) to CBZ. Several postulates were proposed suggesting in induction in the formation pathway of EPO. This study was undertaken to determine whether PB can also modify the elimination kinetics of EPO in monkey. Five rhesus monkeys received an intravenous bolus dose of EPO on day 1, day 5, and day 15. In addition, the animals received an acute loading dose (110 mg) of PB on day 5 followed by 10 daily maintenance doses (35 mg/day). Plasma samples were assayed for PB and EPO by GC/CI/MS. The mean (+/- SD) of plasma clearance (CL), volume of distribution (V), and half-life (t 1/2) during the control period for EPO were 5.57 +/- 2.15 liters/hr, 7.48 +/- 2.50 liters and 0.95 +/- 0.16 hr, respectively. An acute loading dose of PB had no significant effect on any of these pharmacokinetic parameters at p = 0.05. Subchronic administration of PB caused an increase in CL (8.23 +/- 2.03 liters/hr, p less than 0.05), a decrease in t 1/2 (0.67 +/- 0.09, p larger than 0.05 but less than 0.10), and no change in V. This study suggests that PB produces an increase in systemic and intrinsic hepatic clearance of EPO. Therefore, the reported increase in the EPO-CBZ steady-state ratio after PB administration could occur only if the formation clearance of EPO is increased to a greater extent than its elimination clearance.