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

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Abstract
Carbamazepine-10,11-epoxide (CBZ-E) decomposed in gastric juice in vitro. An antacid did not affect the bioavailability of single CBZ [carbamazepine] [a major anticonvulsant] doses given to 3 subjects and was therefore used to neutralize gastric juice when administering CBZ-E. CBZ-E was given orally as a suspension in 2 single doses ranging from 10-200 mg to each of 4 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 h. 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, 1-compartment model with elimination half-lives (t1/2) of 6.1 .+-. 0.9 h. Clearance was 89 .+-. 25 ml .times. kg-1 .times. h-1. Theurinary excretion t1/2 of the trans-CBZ-diol was 12.4 .+-. 0.9 h, which is longer (P < 0.001) than the epoxide plasma t1/2. There was no indication of dose-dependent kinetics of the epoxide. After 200 mg CBZ to the same subjects, plasma CBZ t1/2 was 26.0 .+-. 4.6 h and clearance was 23.4 .+-. 4.6 ml .times. kg-1 .times. h-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.