Pharmacokinetic study of carbamazepine and its epoxide metabolite in humans.

Abstract

A major metabolite of carbamazepine (CBZ), CBZ-10, 11-epoxide (EPO), has been reported to possess anticonvulsant properties. Therefore, the present study was undertaken in order to develop a pharmacokinetic model to predict the behavior of EPO in the body after administration of CBZ. The serum concentration-time curves after oral administration of solution of CBZ (200 mg) or EPO (150 mg) in six healthy subjects showed the characteristic "nose", suggesting that disposition of CBZ or EPO could be described by the two-compartment model. The kinetic parameters of disposition for CBZ and EPO were calculated by the method of Wagner, assuming the absolute bioavailabilities of CBZ and EPO to be 1.0 and 0.81, respectively. Total body clearance and elimination rate constant of EPO were very much larger than those of the parent drug but there was no statistically significant difference in the distribution volume between CBZ and EPO. The formation rate of EPO was calculated by a deconvolution method, and obeyed Michaelis-Menten kinetics. Based on these findings, a pharmacokinetic model of the fate of CBZ and EPO in humans was developed and the time courses of CBZ and EPO in serum after oral administration of three tablet preparations and a solution containing 200 mg of CBZ were simultaneously fitted to this model by solving the differential equations by the Runge-Kutta-Gill method. There was good agreement between calculated and observed serum values, suggesting that the present model is appropriate to describe the formation and disposition of EPO from CBZ. The formation rate constant of EPO (Vmax/Km/V1) was approximately one-fifteenth of the elimination rate constant of EPO. This suggested a flip-flop model in which the formation of EPO was rate-limiting in humans. The observation that the serum concentrations of EPO after administration of CBZ were one-tenth to one-twentieth of those of the parent drug was well explained by the flip-flop kinetics of EPO, together with the large differences in total body clearance and elimination rate constant between CBZ and EPO.