TABLE 4

Pharmacokinetic properties of CTEP, MPEP, MTEP, and fenobam in adult mice and in human and mouse liver microsomes

All data except microsomal clearance are derived from composite pharmacokinetic profiles, with profiles for each compound and route constructed with data from multiple animals (plasma data adult mice, two consecutive plasma samples per animal; brain data adult mice, one brain sample per animal; Microsomal clearance is mean of n = 2 ± S.D.

Allosteric ModulatorDoseCmaxTmaxT1/2ClearanceVssOral BioavailabilityB/P RatioProtein BindingClearance in Microsomes
HumanMouse
mg/kgng/mlhml/min/kgl/kg%%μl/min/mg protein at 1 μM
CTEP3.0 ± 2.84.5 ± 2.1
    Oral4.5 (8.7)a7167.618b (55)a∼100c2.699
    Intravenous1.97710.08342.15.82.699
MPEP276.5 ± 17.7424.0 ± 86.9
    Oral37.79120.6N.A.∼6d0.8e99
    Intravenous18.139300.11.92064.80.8e99
MTEP60.5 ± 2.1401.5 ± 33.2
    Oral34.974350.30.5870.6e85
    Intravenous11.167500.10.2820.80.6e85
Fenobam46.0 ± 4.2442.0 ± 5.7
    Oral31.97960.30.77f2.7e73
    Intravenous10.384100.20.4330.72.7e73
  • N.A., not available.

  • a The longer T1/2 obtained with a higher dose indicates a nonlinear clearance at higher doses.

  • b T1/2 calculated in a time interval 48 to 96 h postdose; for discussion and further calculations, the CTEP half-life of 18 h obtained with an oral dose of 4.5 mg/kg is used because this dose is closer to the doses used in behavioral assays and for chronic drug treatment.

  • c In view of dose-dependent nonlinear clearance observed with high doses, the oral bioavailability values represent a rough estimate.

  • d Based on truncated area under the curve (0–7 h).

  • e Ratio calculated from values recorded 1 h after oral dosing of a dose of 30 mg/kg for each compound.

  • f Estimate.