Abstracts

Rationale: The current study assessed effects of vehicle and dose route on the plasma concentrations of carbamazepine (CBZ) and its major active metabolite (10, 11-epoxide) and subsequent distribution to CSF and brain in rats and dogs. Methods: Sprague Dawley rats or Beagle dogs were given a single dose of CBZ as an oral gavage, intravenous (IV) bolus or slow push infusion. As CBZ is highly insoluble in aqueous solution, CBZ (10 mg/mL) was solubilized in sulfobutylether-β-cyclodextrin (250 mg/mL) for the IV formulation. Plasma, CSF and brain samples were collected at various timepoints, CBZ and 10, 11-epoxide concentrations were measured using LC/MS/MS. Results: In rats, the plasma exposure (AUC) to CBZ after a 40 mg/kg oral dose was 32200 ng*hr/mL compared to after a 10 mg/kg IV infusion or bolus (7130 and 7980 ng*hr/mL, respectively) dose. A similar trend was observed for the 10,11-epoxide metabolite, for which plasma exposures higher than parent were observed for all dose routes (41500 ng*hr/mL for the oral dose and 10900 and 12000 ng*hr/mL, for the infusion or bolus, respectively). The brain-to-plasma concentration ratios ranged from 0.39 - 1.03, and were similar for both analytes across all dose routes. The CSF-to-plasma concentration ratios were also similar across dose routes, but differed for parent (0.13 - 0.22) compared to metabolite (0.45 - 0.53). In the dogs, the plasma exposure to CBZ after a 100 mg/kg oral dose was 15600 ng*hr/mL compared to after a 10 mg/kg IV infusion or bolus (5810 and 6350 ng*hr/mL, respectively). A similar trend was observed for the 10,11-epoxide, for which higher exposures were again observed for all dose routes (45400 ng*hr/mL for the oral dose, and 10900 and 9730 ng*hr/mL for the infusion or bolus, respectively). The CSF-to-plasma concentration ratios were similar across dose routes, but differed for parent (0.20 - 0.28) compared to metabolite (0.46 - 0.67). Conclusions: Overall, CBZ and its 10-11-epoxide metabolite have moderate distribution to CSF (rat and dog) or brain (rat only), with similar distribution between dose routes. These data suggest that the sulfobutylether-β-cyclodextrin excipient in the IV CBZ formulation does not limit the availability of CBZ for distribution into the brain or CSF.