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

1. Although many studies have assessed changes to brain uptake of anti-epileptic 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 the present study, the brain uptake of diazepam and phenytoin 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 with those obtained during acute seizures induced by subcutaneous administration of pentylenetetrazole (PTZ; 90 mg/kg). Diazepam and phenytoin were administered intraperitoneally at doses of 2 and 30 mg/kg, respectively, and brain and plasma concentrations were determined 60 min after administration using liquid chromatography-mass spectrometry. 3. Although the brain uptake of phenytoin was significantly reduced following PTZ administration, no changes were observed in phenytoin disposition in the genetic absence epilepsy model. Similarly, the brain uptake of diazepam was significantly enhanced following PTZ administration, but it was not affected in absence epilepsy. 4. The cerebrovascular plasma volume (assessed by administration of the non-absorbable marker [(14)C]-inulin) was not significantly different in saline-treated compared with PTZ-treated mice and in wild-type compared with mutant R43Q mice. 5. These results demonstrate that although the brain uptake of AEDs may be altered in acute seizure models, similar changes to brain uptake may not be observed in the non-convulsive genetic absence epileptic model.

Pharmacokinetics and brain uptake of AM-36, a novel neuroprotective agent, following intravenous administration to rats.

The plasma pharmacokinetics and brain uptake of the novel neuroprotective agent AM-36 (1-(2-(4-chlorophenyl)-2-hydroxy)ethyl-4-(3,5-bis-(1,1dimethylethyl)-4-hydroxyphenyl) methylpiperazine) were assessed over 72 h following i.v. administration to male Sprague-Dawley rats. At nominal i.v. doses of 0.2, 1 and 3mg kg(-1), AM-36 exhibited an extremely large volume of distribution (18.2-24.6 L kg(-1)) and a long terminal elimination half-life, ranging from 25.2 to 37.7 h. Over this dose range, AM-36 exhibited linear pharmacokinetics, with no apparent change in clearance, volume of distribution or dose-normalised area under the plasma concentration - time curve. AM-36 was very highly bound to plasma proteins (> 99.6%); however, this did not appear to affect the ability of AM-36 to permeate the blood-brain barrier. Following a single i.v. dose of AM-36 at 3mg kg(-1) to rats, brain concentrations were detected for up to 72 h, and the brain-to-plasma ratios were high at all time points (ranging from 8.2 at 5 min post-dose to 0.9 at 72 h post-dose). The very high brain uptake of AM-36 supports previous in-vivo efficacy studies demonstrating the neuroprotective effects of this compound when administered to rats with middle cerebral artery occlusion.