TABLE 1

Comparison of parent and metabolite in vitro cytochrome P450 K_i values for Pfizer clinical development candidates

			Parent			Metabolite
Parent ID	Metabolite Structure	Cytochrome P450	I	K_i	I/K_i	I	K_i	I/K_i	Clinical DDI^{^a}
			µM	µM		µM	µM
PF-01	O-desmethyl	1A2	0.51	>100^{^b}	<0.005	0.98	65	0.015	2D6, D, 1.35
		2D6		35	0.015		>100^{^b}	<0.001
PF-02	N-desmethyl	3A4	0.36	69	0.005	0.060	>100^{^b}	<0.0001	No DDI study
PF-03	O-glucuronide	2C9	0.007	25	0.00028	0.080	>100^{^b}	<0.0008	3A4, A, <1.2
		2C19		13	0.0005		>100^{^b}	<0.0008
		2D6		4	0.0018		>85^{^b}	<0.0009
		3A4		4	0.0018		>85^{^b}	<0.0009
PF-04	N-desmethyl	1A2	0.085	>30^{^b}	<0.003	0.004	7.5	0.00052	No DDI study
		2B6		9	0.0094		7	0.00056
		2C8		8	0.011		14	0.00028
		2C9		2.9	0.029		5	0.00078
		2C19		1.6	0.053		5.5	0.00071
		2D6		3.1	0.027		4.8	0.00081
		3A4		2.7	0.031		4.2	0.00093
	N-oxide	1A2	0.085	>30^{^b}	<0.003	0.006	>30^{^b}	<0.0002	No DDI study
		2B6		9	0.0094		>30^{^b}	<0.0002
		2C8		8	0.011		>30^{^b}	<0.0002
		2C9		2.9	0.029		>30^{^b}	<0.0002
		2C19		1.6	0.053		>30^{^b}	<0.0002
		2D6		3.1	0.027		2.3	0.0024
		3A4		2.7	0.031		>30^{^b}	<0.0002
PF-05	Methyl catechol	2D6	1	4.3	0.233	0.33	11	0.030	No DDI study
PF-06	N-desethyl	2C8	0.14	2.6	0.054	0.41	>30^{^b}	<0.01	No DDI study w/2C8/2C9
		2C9		3.7	0.038		>30^{^b}	<0.01	3A4, M and EE both <1.2
		3A4		9.5	0.015		>30^{^b}	<0.01
PF-07	Cleaved acid	2D6	0.11	0.09	1.2	2.2	>30^{^b}	< 0.08	2D6, D, 2.2
PF-08	Cleaved acid^(a)	3A4	0.87	0.39	2.2	41.8	>30^{^b}	<1	3A4, M 1.4, EE 1.3
	Cleaved acid^(b)	3A4		0.39	2.2	2.35	>30^{^b}	<0.08
PF-09^{^d}	Alcohol	CYPs	5.78	>100^{^b}	<0.06	0.14	>100^{^b}	<0.001	No DDI study
PF-10	N-desmethyl	3A4	0.025	>49^{^b}	<0.0005	0.001	>100^{^b}	<0.00009	No DDI study
PF-11^{^e}	N-desethyl	1A2	0.21	5.4	0.039	0.12	5.8	0.021	No DDI study
		2A6		140	0.0015		140	0.00086
		2C8		28	0.0075		52	0.0023
		2C9		>150^{^c}	< 0.003		79	0.0015
		2C19		110	0.0019		78	0.0015
		2D6		24	0.0088		18	0.0067
		3A4/5		54	0.0039		69	0.002
PF-12	Hydroxy	1A2	0.0015	>20^{^b}	<0.00008	0.037	>25^{^b}	<0.001	No DDI study
		2D6		>20^{^b}	<0.00008		>25^{^b}	<0.001
		3A4		>20^{^b}	<0.00008		>25^{^b}	<0.001
		2C8		4.8	0.00031		>25^{^b}	<0.001
		2C9		>20^{^b}	<0.00008		11	0.0034
		2C19		0.59	0.0025		3.7	0.010

A, atorvastatin; D, desipramine; EE, ethinyl estradiol; M, midazolam.
↵^a Conducted clinical DDI studies listed, cytochrome P450, substrate in clinical study, reported AUC_I/AUC of victim drug in clinical DDI study.
↵^b K_i reported as more than the highest incubation concentration.
^c K_i estimated to be >150 μM.
↵^d PF-09 and metabolite were tested as inhibitors of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, and K_i was reported as more than the highest concentration tested (100 µM).
↵^e PF-11 and metabolite were tested as inhibitors of CYP2B6, CYP2E1, and CYP4A9/11, and K_i was estimated to be >150 µM.