Le. Riad et Rj. Sawchuk, PARTIAL AREA DIFFERENCE ANALYSIS FOR ESTIMATING ELIMINATION RATE CONSTANTS AND DISTRIBUTION VOLUMES OF METABOLITES, Journal of pharmaceutical sciences, 87(6), 1998, pp. 769-773
The true elimination rate constant of a metabolite is calculated using
a partial area difference analysis. A linear pharmacokinetic model wh
ich describes clearances of parent and metabolite is developed. The mo
del makes no restrictions on the route of administration bf the parent
but requires time-invariant kinetics for both parent and metabolite.
Carbamazepine (CBZ), an antiepileptic, is metabolized to the 10,11-epo
xide (CBZE), which is further hydrated to the trans-dihydrodiol (CBZD)
. Plasma data of the metabolites after a 200-mg single oral dose of Te
gretol chewable tablets is used to demonstrate the applicability of th
e method. Elimination rate constants calculated using partial area ana
lysis 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-limi
ted disappearance of CBZD. The elimination rate constants for CBZE and
CBZD calculated using partial areas are comparable to those in the li
terature determined after oral administration of CBZE. Volumes of dist
ribution 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.