TABLE 4

Predicted versus observed AUC ratios (AUC_I/AUC) calculated with the in vitro-based model and in vivo information-guided prediction approach

In vitro (P), only the data of the parent drugs were included in the in vitro-based prediction approach and total systemic C_max was used to estimate perpetrator concentration available to the enzyme; in vitro (P + M), both the data of the parent drug and metabolites were included in the in vitro-based prediction approach; in vitro UHI (P + M), unbound hepatic inlet concentration was used to estimate perpetrator concentration available to the enzyme.

Inhibitors (Parent Drug)	Inhibitors (Metabolites)	Inhibitor Dose	Victim Drug	P450	Observed AUC_I/AUC	Predicted AUC_I/AUC				References for Observed AUC_I/AUC
Inhibitors (Parent Drug)	Inhibitors (Metabolites)	Inhibitor Dose	Victim Drug	P450	Observed AUC_I/AUC	In Vitro (P)	In Vitro (P + M)	In Vitro UHI (P + M)	IVIP	References for Observed AUC_I/AUC
		mg/kg
Casopitant	Hydroxycasopitant	30	Midazolam	3A	1.76	1.36	1.41	1.31	1.74	Zamuner et al., 2010
Diltiazem	N-Desmethyldiltiazem	240	Midazolam	3A	3.88^{^a}	1.38/15.99^{^b}	1.56/20.73^{^b}	1.59/22.98^{^b}	3.91	Backman et al., 1994; Zhang et al., 2009b
Erythromycin	N-Desmethyl erythromycin	1500	Midazolam	3A	4.12^{^a}	1.57/22.23^{^b}	1.57/23.41^{^b}	1.63/23.09^{^b}	4.72	Olkkola et al., 1993; Zimmermann et al., 1996
Itraconazole	Hydroxyitraconazole	200	Midazolam	3A	7.86^{^a}	19.52	21.34	13.61	8.93	Olkkola et al., 1994, 1996; Backman et al., 1998
Itraconazole	Hydroxyitraconazole	200	Simvastatin	3A	18.61	110.66	149.84	47.38	18.26	Neuvonen et al., 1998
Ranolazine	O-Desmethylranolazine	2000	Simvastatin	3A	1.59	2.72	2.79	3.66	1.24	Jerling et al., 2005
Bupropion	Erythrohydrobupropion, hydroxybupropion, threohydrobupropion	150	Desipramine	2D6	5.21	1.03	1.76	1.46	6.67	Reese et al., 2008
Fluoxetine	Norfluoxetine	20	Desipramine	2D6	4.42	2.09	3.29	1.47	4.67	Preskorn et al., 1994
Quinidine	Quinidine N-oxide, 3-hydroxyquinidine	50^{^c}	Desipramine	2D6	3.14	5.27	5.29	5.64	2.64	Ayesh et al., 1991
Sertraline	N-Desmethylsertraline	50	Desipramine	2D6	1.30^{^a}	1.00	1.01	1.00	1.54	Preskorn et al., 1994; Alderman et al., 1997
Sertraline	N-Desmethylsertraline	150	Imipramine	2D6	1.68	1.00	1.01	1.00	1.26	Kurtz et al., 1997
Venlafaxine	N-Desmethylvenlafaxine	150	Imipramine	2D6	1.28	1.00	1.00	1.12	1.17	Albers et al., 2000
Amiodarone	N-Desethylamiodarone	200	Phenytoin	2C9	1.40	1.01	1.36	1.02	1.30	Nolan et al., 1989
Sulfinpyrazone	Sulfinpyrazone sulfide, Sulfinpyrazone sulfone	400	S-Warfarin	2C9	1.82^{^a}	1.16	2.24	1.01	1.49	O'Reilly, 1982; Toon et al., 1986

↵a An algebraic mean of the observed AUC_I/AUC was used if multiple studies are reported for a single combination of substrate and inhibitor (same dose of inhibitor was used in these studies).
↵b The data on the left were calculated based on the reversible inhibition model, whereas the data on the right were based on the irreversible inhibition model.
↵c Single dose of quinidine was administrated to the subjects in this study.