TABLE 2

Data of learning set 1 (data selected to calculate the IR of all CYP2C9 inhibitors) and learning set 2 (data selected to calculate the CR of remaining CYP2C9 substrates)

Substrates	Inhibitors	Dose and Regimen^{^a}	IR	CR	AUC_I/AUC	References^{^b}
		mg/day, days
Learning set 1^{^c}
S-Warfarin	Amiodarone	300, 3	0.31	0.69	1.27	Heimark et al., 1992
		400, 3	0.76	0.69	2.11	O'Reilly et al., 1987
S-Warfarin	Benzbromarone	50, unknown	0.78	0.69	2.15	Takahashi et al., 1999b
S-Warfarin	Bucolome	300, unknown	1.00	0.69	3.29	Takahashi et al., 1999a
S-Warfarin	Cimetidine	1200, 3/15	0.33	0.69	1.30^{^d}	O'Reilly, 1984; Sax et al., 1987
Tolbutamide	Diltiazem	60, 0	0.11	0.84	1.10	Dixit and Rao, 1999
S-Warfarin	Fluconazole	100, 7	0.38	0.69	1.35	Black et al., 1996
		200, 7	0.67	0.69	1.86	Neal et al., 2003
		300, 7	0.72	0.69	2.00	Neal et al., 2003
		400, 7	0.94	0.69	2.84	Neal et al., 2003
Diclofenac	Fluvastatin	40, 7	0.42^{^e}	0.48	1.25	Transon et al., 1995
Tolbutamide	Fluvastatin	40, 15	0.00^{^e}	0.84	1.00	Appel et al., 1995
Tolbutamide	Fluvoxamine	75, 3	0.22	0.84	1.23	Madsen et al., 2001
		150, 3	0.40	0.84	1.50	Madsen et al., 2001
Tolbutamide	Ketoconazole	200, 7	0.52	0.84	1.77	Krishnaiah et al., 1994
S-Warfarin	Miconazole	125, 3	1.00	0.69	4.72	O'Reilly et al., 1992
S-Warfarin	Paroxetine	30, 14	0.09	0.69	1.07	Bannister et al., 1989
Phenytoin	Sertraline	200, 17	0.21	0.75	1.19	Rapeport et al., 1996
Tolbutamide	Sulfaphenazole	1000, 3/1	0.91	0.84	4.19^{^d}	Back et al., 1988; Veronese et al., 1990
Tolbutamide	Sulfinpyrazone	800, 7	0.48	0.84	1.67	Miners et al., 1982
Phenytoin	Voriconazole	800, 9	0.60	0.75	1.81	Purkins et al., 2003
Learning set 2^{^f}
Losartan	Fluconazole	200, 9/3	0.67	0.47	1.47^{^d}	Kazierad et al., 1997; Kaukonen et al., 1998
Zafirlukast	Fluconazole	200, 2^{^g}	0.67	0.56	1.60	Karonen et al., 2012
Glimepiride	Fluconazole	200, 3^{^g}	0.67	0.87	2.38	Niemi et al., 2001
Etravirine	Fluconazole	200, 7	0.67	0.69	1.86	Kakuda et al., 2011

↵a Milligrams per day, the daily doses of the inhibitors; days, the duration of the multiple dosing before administration of substrates. Single dose is shown as 0 days.
↵b The references are only shown in Supplemental Material 3.
↵c Only the DDIs associated with typical CYP2C9 substrates (S-warfarin, tolbutamide, diclofenac, and phenytoin) were included in the learning set 1. In learning set 1, IR of all CYP2C9 inhibitors were calculated by equation 1 using known CR and AUC_I/AUC values.
↵d An algebraic mean of the 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).
↵e Two IR values of fluvastatin were calculated and the mean value was used in the further analysis.
↵f In learning set 2, CR of the remaining CYP2C9 substrates (not included in Table 1) were calculated by eq. 3 using known IR and AUC_I/AUC values.
↵g 400 mg on the first day.