TABLE 1

Physicochemical properties, abundance, and estimated fm of amine metabolites

Structures of drugs and their metabolites are provided in Supplemental Table 1. References provided in Supplemental Material.

Drug	cLogD	tPSA	Metabolite	cLogD	tPSA	M/P	f_m	Ref
Amiodarone	5.87	42.7	N-Desethylamiodarone	5.2	51.5	1*		McDonald et al., 2012
			Didesethylamiodarone	5.25	65.5	0.05*
Amitriptyline	2.64	3.24	Nortriptyline	1.49	12	(CYP2C19) EM: 0.43–0.99; PM: 0.13		Burch and Hullin, 1981; Venkatakrishnan et al., 2001; Jiang et al., 2002
Atomoxetine	0.77	21.3	Desmethylatomoxetine	1.39	35.3	(CYP2D6) EM:0.06; PM:0.38	0.03	Sauer et al., 2003, 2005; FDA Clinical Pharmacology Review^a
Azelastine	1.57	35.9	Desmethylazelastine	1.63	44.7	0.41		Product label
Azimilide	2.66	72.6	N-Desmethylazilimide	1.13	81.39	NR	0.04	Riley et al., 2005
Buspirone	1.24	69.6	1-Pyrimidinylpiperazine	−0.46	41.1	44 to 57		Jajoo et al., 1989; Dockens et al., 2006
Citalopram	1.35	36.3	Desmethylcitalopram	0.014	45.1	(CYP2C19) PM:0.24; EM:0.49		Herrlin et al., 2003; Yu et al., 2003
			Didesmethylcitalopram	0.003	45.1	(CYP2C19) EM:0.07; PM:0.05
Clobazam	1.22	40.6	Norclobazam	1.42	49.4	2.3		Levy et al., 1983
Clomipramine	2.95	6.48	Desmethylclomipramine	1.87	15.3	0.37		Nagy and Johansson, 1977
Clozapine	3.5	30.9	Desmethylclozapine	3.27	39.7	0.32	0.17	Chung et al., 1993
Delavirdine	1.77	119	Desisopropyldelavirdine	1.59	133	SD:1.1; MD:0.14		Borin et al., 1997a,b; Morse et al., 1997
Diazepam	2.8	32.7	Desmethyldiazepam	2.78	41.5	0.35–1.1		Perucca et al., 1994; Kosuge et al., 2001; Saari et al., 2007
Diltiazem	3.36	84.4	N-Desmethyldiltiazem	2.07	93.2	0.35	0.49	Sugihara et al., 1984; Yeung et al., 1990
Dothiepin	2.54	28.5	N-Desmethyldothiepin	1.39	37.3	0.54		Maguire et al., 1981
Doxepin	2.06	12.5	Desmethyldoxepin	0.91	21.3	0.6–1.4		Kirchheiner et al., 2005
Enzalutamide	3.17	99.74	Desmethylenzalutamide	2.98	109	1.60		Product label
Elzasonan	3.24	52.1	Desmethyl elzasonan	2.19	60.9	0.19	NR	Kamel et al., 2010
Fenfluramine	0.91	12	Desethylfenfluramine	0.33	26	0.36–0.37		Caccia et al., 1985
Fentanyl	2.61	23.5	Norfentanyl	−0.44	32.3	2.9		Yeung et al., 2011
Fluoxetine	1.41	21.3	Norfluoxetine	2.12	35.3	0.4–9.4		Hamelin et al., 1996; Ouellet et al., 1998; Fjordside et al., 1999; Moraes et al., 1999; Gupta et al., 2004
Halofantrine	6.93	23.5	Desbutylhalofantrine	3.79	32.3	1.3		Yeung et al., 2011
Imatinib	2.49	86.3	Desmethylimatinib	1	95.1	0.16	0.15	Gschwind et al., 2005
Imipramine	2.34	6.48	Desipramine	1.27	15.3	1.1		Sutfin et al., 1984,1988; Wells et al., 1986; Spina et al., 1997
Itraconazole	4.93	101	Dealkylitraconazole	3.51	110	0.05		Templeton et al., 2008
Ivabradine	3.32	60.1	Desmethylivabradine	2.37	69.3	0.38–0.49		Portoles et al., 2006a,b
Loratadine	3.9	42.4	Desloratidine	0.84	24.3	2.3	0.55	Brannan et al., 1995; Ramanathan et al., 2007a
Loxapine	2.23	28.1	Desmethylloxapine	1.79	36.7	0.24		Simpson et al., 1978; Cheung et al., 1991
Lumefantrine	7.42	23.5	Desbutyllumefantrine	4.76	32.3	0.05		McGready et al., 2006
Mianserin	0.76	6.48	Desmethylmianserin	0.49	15.3	0.61		Pinder and Van Delft, 1983a,b
Mirtazapine	0.28	19.4	Desmethylmirtazapine	−0.35	28.2	0.47–0.75	0.25	Timmer et al., 2000
Nefazodone	3.89	51.6	m-Chlorophenylpiperazine	0.56	15.3	0.09–0.19		Barbhaiya et al., 1995,1996a,b
Olanzapine	2.35	59.1	Desmethylolanzapine	2.21	67.9	NR	0.04	Kassahun et al., 1997
Otenabant (CP-945598)	4.71	102	N-desethylotenabant	3.63	116	4.6		Miao et al., 2012
Oxybutynin	4.15	49.8	Desethyloxybutynin	4.39	58.6	R:21.5; S:8.3		Zobrist et al., 2001
Propafenone	1.37	58.6	Despropylprofenanone	0.68	72.6	0.06–0.18		Kates et al., 1985; Dilger et al., 1999
Ranitidine	−1.07	112	Desmethylranitidine	−2.22	120	0.06	0.01	Prueksaritanont et al., 1989; Product label
Ranolazine	−1.28	74.3	Desalkylranolazine	−2.16	53.9	0.33–0.37		Abdallah and Jerling, 2005; Jerling and Abdallah, 2005; Jerling et al., 2005
Regalinide	1.99	78.87	N-Dealkylregaplinide (M1)	−0.58	101.65	0.06	0.04	Honkalammi et al., 2011
Rosiglitazone	1.93	96.8	Desmethylrosiglitazone	1.39	106	0.58–1.2	0.21	Cox et al., 2000; Kirchheiner et al., 2006
Sertraline	3.04	12	Desmethylsertraline	3.17	26	1.2–1.7		Hamelin et al., 1996
Sibutramine	3.24	3.24	Desmethylsibutramine	2.21	12	3.8		Kim et al., 2009; Bae et al., 2011
			Didesmethylsibutramine	1.89	26	12
Sildenafil	2.45	118	Desmethylsildenafil	0.97	126	0.5	0.22	Muirhead et al., 2002
			Cleaved piperazine ring	−1.24	135	0.27	0.22
Sunitinib	0.44	77.2	Desethylsunitinib	−0.91	86	0.4	0.32	Speed et al., 2012
Tamoxifen	3.83	12.5	Desmethyltamoxifen	3.19	21.3	1.8		Yeung et al., 2011
			Didesmethyltamoxifen	3.11	35.3	0.37
Terbinafine	5.46	3.24	Desmethylterbinafine	5.1	12	0.9		Robbins et al., 1996
Tramadol	0.29	32.7	Desmethyltramadol	−1.11	41.5	0.27		Ardakani et al., 2008; de Moraes et al., 2012
Udenafil	−1.21	126	Desalkyludenafil	0.77	137	1.2–0.7		Shin et al., 2010
Vardenafil	3.45	118	Desethylvardenafil	1.64	126	0.73		Ku et al., 2009
Verapamil	2.46	63.9	Norverapamil	1.35	72.7	1.0–1.3		Abernethy et al., 2000
			D617	−0.69	54.3	0.85–1.2
			D620	−1.29	30.5	0.32–0.46
Zimelidine	2.44	16.1	Desmethylzimelidine	1.38	24.9	3		Brown et al., 1980
Zolmitriptan	−1.47	57.4	Desmethylzolmitriptan	−2.97	66.2	0.6	0.04	Dixon et al., 1997; Seaber et al., 1997
Zopiclone	2.63	91.8	Desmethylzopiclone	1.57	101	0.2	0.17	Fernandez et al., 1995; Mistri et al., 2008

SD, single dose; MD, multiple dose; R, R-enantiomer; S, S-enantiomer; NR, not reported.
* Denotes M/P ratio from single time point concentration.
↵^a http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-411_Strattera_biopharmr_P2.pdf