TABLE 3

In vitro inhibition data in rat microsomes and hepatocytes obtained for substrates and inhibitors of CYP2C9, CYP2D6, and CYP3A4

In the present study microsomal values represent mean (n = 3) ± S.D. and hepatocyte values represent mean (n = 4) ± S.D.

P450 Inhibitor
Pathway
Unbound Ki Values
Cell-to-Medium Ratio
Fraction Unbound in Incubation (fuinc)
Ki Ratioa
Microsomes
Hepatocytes
Microsomes
Hepatocytes
μM
Miconazole Hydroxy-tolbutamide 0.22 ± 0.06 0.22 ± 0.08 6000 0.06b 0.06c 1
Fluconazole Hydroxy-tolbutamide 29 ± 0.4 16 ± 1.0 4.2 1b 0.99c 1.81
1-Hydroxy midazolam 26 30 0.87
4-Hydroxy midazolam 17.8 9 1.98
Phenytoin 3.5 1.31 2.67
Ketoconazole Hydroxy-tolbutamide 0.88 ± 0.30 0.44 ± 0.10 1200 0.23b 0.26c 2
1-Hydroxy midazolam 0.08 1.19 0.07
4-Hydroxy midazolam 0.05 0.04 1.25
Phenytoin 0.19 0.28 0.68
Quinine Dextrorphan 1.6 ± 0.65d 1.4 ± 0.82d 143e 0.85f 0.85g 1.14
Dextrorphan 3.0 ± 1.6h 8.3 ± 1.32h 0.36
3-Methoxymorphinan 5.7 ± 2.6 6.2 ± 2.13 0.92
Fluoxetine Dextrorphan 0.06 ± 0.03d 0.15 ± 0.05d 2010e 0.51f 0.28g 0.4
Dextrorphan 0.97 ± 0.47h 0.58 ± 0.22h 1.67
3-Methoxymorphinan 1.5 ± 1.3 0.94 ± 0.22 1.60
Fluvoxamine Dextrorphan 0.26 ± 0.02d 0.44 ± 0.08d 577e 0.79f 0.58g 0.59
Dextrorphan 1.4 ± 0.4h 1.6 ± 0.21h 0.88
3-Methoxymorphinan
3.3 ± 1.38
0.99 ± 0.27
3.33

  • ↵ a Ki ratio is represented as microsomal Ki/hepatocyte Ki.

  • ↵ b fuinc determined at 0.5 mg/ml.

  • ↵ c fuinc determined at 0.5 × 106 cells/ml.

  • ↵ d Inhibition data for the high-affinity, low-capacity dextrorphan pathway.

  • ↵ e Taken from Hallifax and Houston (2007).

  • ↵ f fuinc determined at 0.1 mg/ml.

  • ↵ g fuinc determined at 0.25 × 106 cells/ml.

  • ↵ h Inhibition data for the low-affinitiy, high-capacity dextrorphan pathway.