The dose dependency of carbamazepine pharmacokinetics was characterized in rats, a common test animal for antiepileptic drug efficacy. With a randomized Latin square schedule, 5, 10, and 20 mg/kg doses of carbamazepine were injected intravenously into six Sprague-Dawley rats followed by the administration of a 5 or 10 mg/kg i.v. dose of CBZ-E to each rat. Following administration, the concentrations of CBZ and carbamazepine-10,11-epoxide (CBZ-E) in whole blood were determined by a reverse-phase HPLC assay. Plasma protein binding of both carbamazepine and CBZ-E was linear over the concentration range observed in this study. Carbamazepine concentration-time plots were log-linear, but the slopes were not parallel. Carbamazepine total-body clearances were 15.1 +/- 3.26, 13.4 +/- 5.66, and 10.0 +/- 3.11 ml/min/kg at the 5, 10, and 20 mg/kg doses, respectively (significance of difference between the 5 and the 20 mg/kg dose = 0.06 less than P less than 0.05; Kruskal-Wallis test, Dunn's procedure). However, the formation clearance to CBZ-E did not change, suggesting that metabolism via other pathways was decreased at higher carbamazepine doses.