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compounds was assessed in Sprague–Dawley rats (n = 3). Compounds were
dosed intravenously at 1 mg/kg and orally by gavage at 2 mg/kg. Blood was
taken at eight time points (5, 15, 30 min, 1, 2, 4, 6, 8 h) and collected into EDTA
containing tubes and plasma was generated using standard centrifugation
techniques. Plasma proteins were precipitated with acetonitrile and drug
concentrations were determined by LC–MS/MS. Data was fit by WinNonLin
using
a noncompartmental model and basic pharmacokinetic parameters
including peak plasma concentration (Cmax), oral bioavailability, exposure
(AUC), half-life (t1/2), clearance (CL), and volume of distribution (Vd) were
calculated. CNS exposure was evaluated in C57Bl6 mice (n = 3). Compounds
were dosed at 10 mg/kg intraperitoneally and after 2 h blood and brain were
collected. Plasma was generated and the samples were frozen at ꢀ80 °C. The
plasma and brain were mixed with acetonitrile (1:5 v/v or 1:5 w/v,
respectively). The brain sample was sonicated with a probe tip sonicator to
break up the tissue, and samples were analyzed for drug levels by LC–MS/MS.
Plasma drug levels were determined against standards made in plasma and
brain levels against standards made in blank brain matrix. All procedures were
approved by the Scripps Florida IACUC.