Pharmacokinetics of carbamazepine polymorphs and dihydrate in rats, related to dogs and humans

Abstract

Species differences in the oral pharmacokinetics and absolute bioavailability (F ( abs )) of carbamazepine polymorphs (form I and form III) and dihydrate were studied. The pharmacokinetics of each form was investigated in rats following a single oral/intravenous administration of 10 mg/kg and an oral dose of 80 mg/kg, which were compared with the published data obtained from dogs and humans. No significant differences were found in their C (max), T (max), AUC(0-∞) and F ( abs ) among the forms at the low dose. However, significant differences were observed at the high dose. The Fabs of each form was markedly reduced with increasing of doses in species (e.g. F ( abs ) in rats ranged from > 82% to 38.4%-56.0%). At a comparable dose, the C (max), and AUC(0-∞) of rats and humans were about 3-10 times higher than in dogs. The absorption rate of form III in rats exhibited a similar trend to that in humans, and was far higher in dogs. A multi-peak phenomenon in plasma curves was observed in rats and humans, but not in dogs. In conclusion, rats appear to be a better predictor of carbamazepine polymorphs absorbed in humans, and form III may be more suitable as a pharmaceutical crystal.