Carbamazepine Metabolism in Humans

Abstract

Free and total carbamazepine (CBZ) and carbamazepine-epoxide (CBZ-EP) plasma levels were obtained on 113 patients with epilepsy (18-61 years old) controlled on either monotherapy or coadministration with either phenobarbital (PB), phenytoin (PHT), valproic acid (VPA), or all three. A subset of patients were administered tetradeuterium labeled CBZ to evaluate the effects of autoinduction and coadministration of VPA on the kinetics of CBZ and its metabolite CBZ-EP. Polytherapy had variable effect on free and total CBZ plasma levels compared to monotherapy. Coadministered PHT-(co-PHT), or all three anticonvulsants together (PHT, PB and VPA: co-AEDs) decreased free and total CBZ plasma levels. No change was noted for coadministered VPA (co-VPA). Compared to monotherapy the free and total CBZ-EP levels increased with co-VPA, less with coadministered PB (co-PB), and no change with co-PHT or co-AEDs. Protein binding of CBZ and CBZ-EP was not affected by any antiepileptic drugs studied. The free and total CBZ-EP/CBZ ratio was tripled with co-VPA or co-AED''s, and doubled with co-PHT or co-PB. Isotope labeling did not demonstrate any differences in half-life (t 1/2), plasma clearance (Cl), or volume of distribution (Vd). Compared to naive controls, monotherapy and co-VPA decreased CBZ t 1/2 by 50%, and more than doubled the CBZ Cl without a significant change in the Vd. Autoinduction is one explanation for these changes with chronic CBZ therapy. With the addition of VPA to chronic CBZ therapy no change was noted on the t 1/2, Cl, Vd, or mean CBZ plasma level, but the CBZ-EP plasma level more than quadrupled. This suggests a decrease in CBZ-EP clearance. These data support the autoinduction phenomena for chronic CBZ therapy and the concept of VPA inhibiting carbamazepine-epoxide metabolism.