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 K_i Values			Cell-to-Medium Ratio	Fraction Unbound in Incubation (fu_inc)			K_i Ratio^a
P450 Inhibitor	Pathway			Microsomes	Cell-to-Medium Ratio	Hepatocytes		Microsomes	K_i Ratio^a	Hepatocytes
		μM
Miconazole	Hydroxy-tolbutamide	0.22 ± 0.06	0.22 ± 0.08	6000	0.06^b	0.06^c	1
Fluconazole	Hydroxy-tolbutamide	29 ± 0.4	16 ± 1.0	4.2	1^b	0.99^c	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	0.23^b	0.26^c	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 ± 0.65^d	1.4 ± 0.82^d	143^e	0.85^f	0.85^g	1.14
	Dextrorphan	3.0 ± 1.6^h	8.3 ± 1.32^h				0.36
	3-Methoxymorphinan	5.7 ± 2.6	6.2 ± 2.13				0.92
Fluoxetine	Dextrorphan	0.06 ± 0.03^d	0.15 ± 0.05^d	2010^e	0.5^f	0.28^g	0.4
	Dextrorphan	0.97 ± 0.47^h	0.58 ± 0.22^h				1.67
	3-Methoxymorphinan	1.5 ± 1.3	0.94 ± 0.22				1.60
Fluvoxamine	Dextrorphan	0.26 ± 0.02^d	0.44 ± 0.08^d	577^e	0.79^f	0.58^g	0.59
	Dextrorphan	1.4 ± 0.4^h	1.6 ± 0.21^h				0.88
	3-Methoxymorphinan	3.3 ± 1.38	0.99 ± 0.27				3.33

↵ a K_i ratio is represented as microsomal K_i/hepatocyte K_i
↵ b fu_inc determined at 0.5 mg/ml
↵ c fu_inc 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 fu_inc determined at 0.1 mg/ml
↵ g fu_inc determined at 0.25 × 10⁶ cells/ml
↵ h Inhibition data for the low-affinity, high-capacity dextrorphan pathway