PARTIAL AREA DIFFERENCE ANALYSIS FOR ESTIMATING ELIMINATION RATE CONSTANTS AND DISTRIBUTION VOLUMES OF METABOLITES

Citation
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
Citations number
18
Categorie Soggetti
Chemistry Medicinal","Pharmacology & Pharmacy",Chemistry
ISSN journal
00223549
Volume
87
Issue
6
Year of publication
1998
Pages
769 - 773
Database
ISI
SICI code
0022-3549(1998)87:6<769:PADAFE>2.0.ZU;2-V
Abstract
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.