Influence of phenobarbital on pharmacokinetics of carbamazepine and its epoxide metabolite in the rabbit

Abstract

The influence of coadministration of phenobarbital (PB) on the disposition of carbamazepine (CBZ) and its active metabolite, CBZ-10, 11-epoxide (EPO), were investigated by use of rabbits. The disposition of CBZ or EPO after intravenous injection is well described by a one-component model, and the formation and elimination of EPO after the administration of CBZ followed linear first-order kinetics at doses below 20 mg/kg. The total plasma clearance (CL), volume of distribution (Vd), and half-life (T1/2) of CBZ were 1.219±0.470 (mean±S.D.) l/h/kg, 1.086±0.287 l/kg, and 0.648±0.134 h, respectively. The values for CL, Vd, and T1/2 of EPO were 0.340±0.210 l/h/kg, 1.025±0.138 l/kg, and 2.569±1.041 h, respectively. The epoxidation rate constant (kf) and fraction (fm) of CBZ biotransformed to EPO were 0.167±0.075 h-1 and 0.152±0.055, respectively, and the area under the plasma concentration (AUC) ratio of EPO to CBZ after intravenous injection of CBZ was 0.575±0.197 for control rabbits. The single intravenous injection of PB (50 mg/kg) at 30 min prior to the administration of CBZ or EPO has no significant effect on any of these pharmacokinetic parameters of CBZ or EPO. However, repeated PB treatment (intraperitoneal injection of 50 mg/kg/d of PB for 7d) caused an increase in CL of CBZ and EPO (2.620±0.345 and 0.588±0.188 l/h/kg), a decrease in T1/2 of CBZ and EPO (0.350±0.078 and 1.189±0.418 h), and no change in Vd of CBZ and EPO (1.328±0.371 and 0.928±0.161 l/kg) compared to those of control rabbits. Although repeated PB treatment increased significantly in kf (0.213±0.069 h-1), there was no singificant change in the AUC ratio of EPO to CBZ (0.568±0.149). This result was well explained by the facts that there was no change of fm values (0.110±0.039) and that the degree in enzyme-inducing effects for CBZ and EPO between repeated PB treatment and control rabbits was the same.