TABLE 1

Summary of noncompartmental pharmacokinetic parameters of potential P450 substrates in dogs (n = 4) in the absence (day 1) and presence of an inhibitor (day 4) dosed once a day for 3 daysa

ParameterTreatment
DayCaffeineMidazolam (p.o.)Midazolam (i.v.)TemazepamBufuralolBufuralol
Dose (mg/kg)11.3 ± 1.00.50 ± 0.100.50 ± 0.101.7 ± 0.30.78 ± 0.131.1 ± 0.2
41.3 ± 1.00.50 ± 0.100.50 ± 0.101.7 ± 0.30.79 ± 0.131.1 ± 0.2
Cmax,obs (ng/ml)11230 ± 26588.9 ± 45.91860 ± 29535.7 ± 31.0407 ± 224205 ± 120
41790 ± 104343 ± 1271700 ± 1570342 ± 180216 ± 167155 ± 164
Tmax,obs (h)12.3 ± 1.30.63 ± 0.250.0330.63 ± 0.250.51.1 ± 1.3
41.2 ± 0.80.50.0330.75 ± 0.291.3 ± 0.61.3 ± 1.2
t1/2 (h)14.2 ± 0.82.4 ± 1.71.3 ± 0.39.0 ± 7.31.3 ± 0.44.3 ± 4.3
46.8 ± 1.21.7 ± 0.42.0 ± 0.83.2 ± 1.21.9 ± 0.22.2 ± 0.7
AUC0–24 (ng × h/ml)110800 ± 85792.5 ± 50.3337 ± 5554.7 ± 50.6525 ± 264408 ± 366
417900 ± 1220760 ± 313871 ± 359685 ± 193550 ± 391390 ± 403
Foral0.274
Inhibitor dose (mg/kg)9.2 ± 1.1b22.2 ± 4.5c22.2 ± 4.4c22.2 ± 4.4c9.7 ± 1.6d11.1 ± 2.2e
Inhibitor AUC0–24 (μg × h/ml)412.8 ± 2.8b272 ± 167c458 ± 314c379 ± 45c230 ± 77d24.3 ± 10.0e
Inhibitor Cmax (μg/ml)40.864 ± 0.177b44.1 ± 27.3c42.8 ± 26.2c43.5 ± 16.0c14.4 ± 4.5d2.06 ± 0.73e
Inhibitor Cavg,obs,0–24 h (μg/ml)40.533b11.3c19.1c15.8c9.58d1.01e

  • ↵a All values represent the mean ± S.D. where applicable.

  • ↵b Fluvoxamine,

  • ↵c ketoconazole,

  • ↵d fluoxetine, and

  • ↵e clomipramine inhibitors.