Brain uptake of diazepam and phenytoin in a genetic animal model of absence epilepsy

SUMMARY 1. While many studies have assessed changes to brain uptake of antiepileptic drugs (AEDs) in chemically and electrically-induced seizure models, there are limited data available on changes to brain uptake of AEDs in spontaneous seizure animal models such as genetic absence epilepsy. 2. In this study, the brain uptake of diazepam (DIAZ) and phenytoin (PHT) was assessed in a genetic mouse model of absence seizures harbouring a human GABA(A) receptor gamma2 subunit gene GABRG2 mutation (R43Q), and results were compared to those obtained during acute seizures induced by subcutaneous administration (90 mg/kg) of pentylenetetrazole (PTZ). DIAZ and PHT were administered intraperitoneally at doses of 2 and 30 mg/kg, respectively, and brain and plasma concentrations determined 60 min post-dose using liquid chromatography-mass spectrometry. 3. While the brain uptake of PHT was significantly reduced following PTZ administration, no alteration to PHT disposition was observed in the genetic absence epilepsy model. Similarly, the brain uptake of DIAZ was significantly enhanced following PTZ administration, however, it was not affected in absence epilepsy. 4. The cerebrovascular plasma volume (assessed by administration of the nonabsorbable marker (14)C-inulin) was not significantly different in saline-treated versus PTZ-treated mice, and in wild-type versus mutant R43Q mice. 5. These results demonstrate that while the brain uptake of AEDs may be altered in acute seizure models, similar changes to brain uptake may not be observed in the nonconvulsive genetic absence epileptic model.