Effect of Four‐Day Treatment with Carbamazepine at Different Dose Levels on Microsomal Enzyme Induction, Drug Metabolism and Drug Toxicity

Abstract

The effect of intraperitoneal injections of 0, 30, 60 and 100 mg/kg of carbamazepine (CBZ), twice a day for 4 days, was studied in 4 groups of 6 male Sprague-Dawley rats per group to evaluate its hepatic enzymatic induction, toxicity and metabolism. Rats were sacrificed on the fifth day and the urines of the last 24 hours were collected. While the activities of hepatic microsomal aminopyrine N-demethylase and epoxide hydratase tended to increase with the dose of CBZ, the cytochrome P-450 content and the activity of aniline hydroxylase however reached a maximum at 60 mg/kg. The percentage of the administered daily dose of CBZ excreted as unchanged CBZ in the urine increased considerably with the dose, while that of metabolites such as carbamazepine-10,11-epoxide (CBZ-E), trans-10,11-dihydrodihydroxycarbamazepine (TDC), and thioethers (T) did not markedly change. These data not only corroborate a maximum in enzyme induction but also suggest a saturation of the induced hepatic enzymes. Urinary T and TDC, representing more than 50% and less than 10%, respectively of the total amount recovered, tend to demonstrate that the glutathione conjugation with the intermediates of CBZ leading to the formation of higher mercapturates could be more important than the epoxide-diol pathway for the metabolism of CBZ under conditions of repeated dosing.