A partial area difference analysis for estimating elimination rate constants and distribution volumes of metabolites

The true elimination rate constant of a metabolite is calculated using a partial area difference analysis. A linear pharmacokinetic model which describes clearances of parent and metabolite is developed. The model makes no restrictions on the route of administration of the parent but requires time-invariant kinetics for both parent and metabolite. Carbamazepine (CBZ), an antiepileptic, is metabolized to the 10,11-epoxide (CBZE), which is further hydrated to the trans-dihydrodiol (CBZD). Plasma data of the metabolites after a 200-mg single oral dose of Tegretol chewable tablets is used to demonstrate the applicability of the method. Elimination rate constants calculated using partial area analysis are 0.087 +/- 0.015 (h-1) and 0.056 +/- 0.014 (h-1) for CBZE and CBZD, respectively. These correspond to an average half-life of 8.0 h for CBZE and 12.4 h for CBZD, which suggest elimination-rate-limited disappearance of CBZD. The elimination rate constants for CBZE and CBZD calculated using partial areas are comparable to those in the literature determined after oral administration of CBZE. Volumes of distribution of CBZE and CBZD are also estimated to be 0.57 +/- 0.11 L/kg and 0.76 +/- 0.24 L/kg, respectively. The higher values observed with CBZD volumes of distribution are attributed to the higher plasma free fraction of the diol relative to CBZE.