Single-dose kinetics and metabolism of carbamazepine-10,11-epoxide.

Carbamazepine-(CBZ)-10,11-epoxide (CBZ-E) was found to decompose in gastric juice in vitro. An antacid did not affect the bioavailability of single CBZ doses given to three subjects and was therefore used to neutralize gastric juice when administering CBZ-E. CBZ-E was given orally as a suspension in two single doses ranging from 10 to 200 mg to each of four healthy subjects. Plasma concentrations of CBZ and CBZ-E were determined with high-performance liquid chromatography. Plasma concentrations and urinary excretion of the end metabolite trans-10,11-dihydroxy-10,11-dihydro-CBZ (trans-CBZ-diol) were measured by mass fragmentography. After dosing with CBZ-E, peak plasma concentrations of the parent compound were reached within 2 hr. Urinary recovery of trans-CBZ-diol was 90 +/- 11% (mean +/- SD) of the dose, indicating almost complete absorption. Plasma kinetics of the epoxide fitted an open one-compartment model with elimination half-lifes (t 1/2s) of 6.1 +/- 0.9 hr. Clearance was 89 +/- 25 ml x kg-1 x hr-1. The urinary excretion t 1/2 of the trans-CBZ-diol was 12.4 +/- 0.9 hr, which is longer (P less than 0.001) than the epoxide plasma t 1/2. There was no indication of dose-dependent kinetics of the epoxide. After 200 mg CBZ to the same subjects, plasma CBZ t 1/2 was 26.0 +/- 4.6 hr and clearance was 23.4 +/- 4.6 ml x kg -1 x hr -1. Of the CBZ dose, 20.5 +/- 2.9% was excreted as the trans-CBZ-diol, which gives an estimate of the percentage of CBZ that is metabolized by the epoxide-diol pathway in healthy subjects. These observations provide a basis for the administration of CBZ-E in patients to assess its clinical effects.