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.

Simultaneous first- and zero-order absorption of carbamazepine tablets in humans.

The absorption kinetics of carbamazepine (5H-dibenz[b,f]azepine-5-carboxamide) in healthy adult volunteers was investigated following a single 400-mg (2 X 200-mg) oral dose of commercially available conventional tablets (Tegretol). Wagner-Nelson plots of the data from all subjects (n = 10) showed that the fraction remaining to be absorbed declined in a biphasic manner, suggesting a mixed order of absorption. A model assuming the absorption of carbamazepine by simultaneous first-order and zero-order rates was used to describe the overall absorption process. Model parameters (and their mean +/- SD values) were: alpha, the fraction of the dose absorbed at a first-order rate (0.646 +/- 0.070); Ka, the first-order absorption rate constant (0.45 +/- 0.13 h-1); and tdur, the duration of the zero-order absorption component (36.0 +/- 4.4 h). If complete absorption can be assumed, then the corresponding average zero-order rate was 4.0 mg X h-1. The results indicate that 35% of the available dose is absorbed at a zero-order rate. These data suggest a prolonged constant rate of absorption due to continued delivery during its transit in the intestine. In addition, an assessment of the mean absorption time, based on the parameters from the model described above, compared closely (7.95 versus 8.44 h) with the mean absorption time estimated from an analysis of the fraction remaining to be absorbed versus time plot using a noncompartmental approach.

Effect of polyethylene glycol 400 on the intestinal permeability of carbamazepine in the rabbit.

Because of the limited solubility of carbamazepine, aqueous solutions are usually prepared using glycols as cosolvents. This research focuses on the effect of varying the composition of polyethylene glycol 400 (PEG-400) in aqueous solutions in rabbit intestinal permeability of carbamazepine in the duodenojejunum and the ascending colon using an in situ perfusion technique. In both segments the intestinal permeability varied inversely with the percentage of PEG-400, when the concentration of carbamazepine in the perfusing solution was maintained constant. The decreased permeability may be explained by a reduction in the thermodynamic activity of carbamazepine with increased concentrations of PEG-400, as well as by reverse solvent drag because of the hyperosmolarity of the perfusing solutions.

Absorptive clearance of carbamazepine and selected metabolites in rabbit intestine.

The intestinal permeability of carbamazepine, an antiepileptic drug, was examined as a function of intestinal site (duodenojejunum vs colon). A "through-and-through" in situ intestinal perfusion technique was adopted using the rabbit as an animal model. Coperfusion of the 10,11-epoxide and the 10,11-transdihydrodiol metabolites along with carbamazepine allowed for an examination of the effect of lipophilicity on intestinal permeability when molecular weight differences are negligible. Our results showed that carbamazepine is absorbed from rabbit duodenojejunum as well as the colon, which may explain the prolonged absorption behavior observed in humans. Also, the absorptive clearance of compounds having similar molecular weights is dependent not only on the lipophilicity but also on the extent of solvent drag during the course of the perfusion.

Simultaneous determination of carbamazepine and its epoxide and transdiol metabolites in plasma by microbore liquid chromatography.

Simultaneous monitoring of carbamazepine and its metabolities is helpful in providing information on the induction process via the epoxide-diol route. The present method involves the liquid-chromatographic analysis of 1.0 mL of plasma for carbamazepine at concentrations of 0.025 to 4.0 mg/L and for both the 10,11-epoxide and 10,11-transdiol metabolites at concentrations of 0.01 to 1.0 mg/L. Weighted regression equations, expressing peak area ratios as a function of concentrations of carbamazepine and its epoxide and transdiol metabolites in the standards, were used to determine concentrations in plasma samples.

Effect of packaging and storage on the stability of carbamazepine tablets.

The effect of packaging and storage on carbamazepine (CBZ) tablets was examined using Tegretol and Tegral, dispensed in strip seals, and Finlepsin, dispensed in bottles. Tegretol and Tegral tablets were stored in their original strips at 40 degrees C, 50 degrees C, and 60 degrees C for 6 months, 3 months, and 1 month, respectively, at 75% relative humidity (RH). Also, tablets were removed from their strips, placed in bottles, and exposed daily to 97% RH at 40 degrees C for 5 min for 30 days. Finlepsin tablets were exposed to 97% RH at 25 degrees C or 40 degrees C for 1 month by removing bottle caps daily for 5 min. Dissolution was used to assess in vitro tablet performance, and high-performance liquid chromatography (HPLC) was used to evaluate the chemical stability of CBZ. Results show that Tegretol tablets were not affected by the tested stress conditions. Tegral tablets, stored in their strips at 50 degrees C or 60 degrees C and 75% RH, showed increased disintegration and dissolution. The effect of 40 degrees C/75% RH for 6 months was similar to 1-month storage at 40 degrees C/97% RH; the tablets hardened and dissolved less than fresh Tegral tablets. Removal of Tegral tablets from their original strips resulted in only 7% dissolved in 60 min. For Finlepsin, the effect of 97% RH at 40 degrees C was more profound than 97% RH at 25 degrees C, but both conditions caused a decrease in dissolution, the extent of which was dependent on tablet position in the bottle. Stressed CBZ tablets, however, showed no change in the chemical stability of CBZ under all tested conditions.