TABLE 4

Physicochemical properties, abundance and estimated fm of arenol metabolites

Structures of drugs and their metabolites are provided in Supplemental Table 3. References provided in Supplemental Material.

Drug	cLogD	tPSA	Metabolite	pK_a	cLogD	tPSA	M/P (Aglycone)	Conjugate³	f_m	Ref
Amoxapine	1.79	36.9	7-Hydroxyamoxapine	11.16	1.68	57.1	0.22–0.44	Yes	0.25	Jue et al., 1982; Kobayashi et al., 1985; Takeuchi et al., 1993
			8-Hydroxyamoxapine	10.35	1.02	57.1	2.4–4.9	Yes	0.33
Atomoxetine	0.77	21.3	Hydroxyatomoxetine	10.33	−0.13	41.5	CYP2D6 EM: 0.01	Yes (CYP2D6 EM: 2.5 & PM: 0.11)	CYP2D6 EM:0.87	Sauer et al., 2003, 2005; FDA Clinical Pharmacology Review^{^a}
Atorvastatin	0.74	112	o-Hydroxyatorvastatin	9.34	1	132	1.4	NR		Whitfield et al., 2011
			p-Hydroxyatorvastatin	10	0.1	132	0.04	NR
Chlorpromazine	3.24	31.8	Hydroxychlorpromazine	9.19	2.65	52	0.58–1.8	Yes (2.2– 4.2)		Yeung et al., 1993
Desipramine	1.21	15.3	Hydroxydesipramine	10	−0.19	35.5	0.22–0.79	Yes (3.3)		DeVane et al., 1981; Spina et al., 1997; Patroneva et al., 2008
Desloratadine	0.84	24.9	Hydroxydesloratadine	9.27	0.49	45.2	0.5	Yes	0.51	Gupta et al., 2004; Ramanathan et al., 2007b
Duloxetine	2.31	49.5	Hydroxyduloxetine	9.97	1.51	69.7		Yes (12)	0.22	Lantz et al., 2003; Knadler et al., 2011
			5-Hydroxy-6-methoxy duloxetine	7.67	1.49	78.9		Yes (5.6)	0.19
Efavirenz	3.03	38.3	Hydroxy efavirenz	7.18	2.38	58.6	0.04	Yes (1.1)	0.24	Mutlib et al., 1999; Cho et al., 2011; FDA Clinical Pharmacology Review^{^b}
Elzasonan	3.24	52.1	5-Hydroxy elsazonan	11.5	3.16	72.3	0	Yes	0.34	Kamel et al., 2010
Granisetron	0.0166	50.2	Hydroxygranisetron	8.9	−0.59	70.4	0.11*	0.26*	0.25	Clarke et al., 1994
Imipramine	2.34	6.48	Hydroxyimipramine	10.2	1.71	26.7	0.37–0.89	Yes (1.9)		Sutfin et al., 1984,1988; Wells et al., 1986; Spina et al., 1997
Lansoprazole	2.58	87.1	Hydroxylansoprazole	11.16	1.9	10.7	CYP2C19 EM:0.1–0.19; PM:0.02			Miura et al., 2004; Zhang et al., 2011
Loxapine	2.23	28.1	7-Hydroxyloxapine	11.16	2.1	48.3	0.68			Simpson et al., 1978; Cheung et al., 1991
			8-Hydroxyloxapine	10.35	1.45	48.3	3
Nelfinavir	7.26	127	Methoxycathecol	8.57	7.28	136	0.05			Zhang et al., 2011
Propafenone	1.37	58.6	Hydroxypropafenone	9.48	1.21	78.8	0.23– 0.5			Kates et al., 1985; Dilger et al., 1999
Propranolol	0.79	41.5	Hydroxypropanolol	10.17	0.25	61.7	0.01–0.09 (without hydrolysis) 2.8 (with hydrolysis)	Yes		Raghuram et al., 1984; Partani et al., 2009
Quetiapine	2.51	73.6	Hydroxyquetiapine	11.18	1.91	93.8	0.1			Gefvert et al., 1998; DeVane and Nemeroff, 2001
Rosiglitazone	1.93	96.8	Hydroxyrosiglitazone	10.3	1.33	117		Yes (2.8)	0.29	Cox et al., 2000; Kirchheiner et al., 2006
Tamoxifen	3.83	12.5	Hydroxytamoxifen	10.35	3.63	32.7	0.035			Yeung et al., 2011
S-warfarin	0.33	63.6	Hydroxywarfarin	8.51	0.36	83.8	0.15			Uno et al., 2008
Amiodarone	5.87	42.7	O-Desalkylamiodarone	4.84	3.33	50.4	0.1	No		McDonald et al., 2012
Ampremilast	0.48	127	Demethoxyampremilast	9.8	−0.032	138	ND	Yes (1.24)	0.39	Hoffmann et al., 2011
Apixaban	4.66	111	Demethoxyapixaban	8.56	4.02	122	ND	Yes (0.25)	0.18	Raghavan et al., 2009
Astemizole	4.12	42.3	Demethoxyastemizole	10.13	3.53	53.3	6.8			Lefebvre et al., 1997
Bosentan	2.36	154	Demethoxybosentan	8.36	2.34	165	0.02–0.05		0.07	Weber et al., 1999; van Giersbergen et al., 2002
Codeine	0.46	41.9	Morphine	9.48	−0.043	52.9	0.003–0.008	Yes (M6G:0.33–0.45; M3G:2–2.6)		Kirchheiner et al., 2007
Dextromethorphan	2.17	12.5	Demethyl-dextromethorphan	10.07	1.71	23.5	CYP2D6 EM: 0.38 (without hydrolysis) 69 (with hydrolysis)	Yes		Bolden et al., 2002; Pope et al., 2004
Encainide	1.62	41.57	O-Demethyencanide	8.34	1.2	52.6	CYP2D6 EM: 1.2			Funck-Brentano et al., 1989
Flecainide	1.05	59.6	Dealkylflecainide	9.28	−0.14	70.6	0.04	Yes	0.23	Munafo et al., 1990
Gefitinib	2.56	68.7	Demethylgefitinib	5.5	1.79	79.7	0.7		0.23	McKillop et al., 2004; FDA Clinical Pharmacology Review^{^c}
Pantoprazole	1.54	106	Demethylpantoprazole	7.69	0.49	117	ND	Yes (0.2– 0.5)		Radhofer-Welte, 1999
Paroxetine	1.48	39.7	4-Hydroxy-3-methoxy paroxetine	10.34	1.04	50.7	NR	Yes		Segura et al., 2003
Ranolazine	1.28	74.3	Demethylranolazine	9.59	0.94	85.3	0.36	Yes		Abdallah and Jerling, 2005; Jerling and Abdallah, 2005; Jerling et al., 2005
Tadalafil	2.71	74.9	4-Hydroxy-3-methoxy tadalafil	9.87	2.85	85.9	0.58 (SD); 1.3 (MD)	Yes		Forgue et al., 2006, 2007
Tramadol	0.29	32.7	Demethyltramadol	10	−0.25	43.7	0.35 - 0.95	No		Ardakani et al., 2008; de Moraes et al., 2012
Venlafaxine	0.76	32.7	Desvenlafaxine	10	−0.0015	43.7	EM: 4.0–6.0; PM: 0.35	Yes	0.56	Howell et al., 1993; Patat et al., 1998; Hynninen et al., 2008

Yes, presence of conjugate of the metabolite in circulation; NR, not reported; the number represents M/P ratio of the metabolite conjugate to parent.
* 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.
↵^b http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20972biopharm_review.pdf.
↵^c http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/21-399_IRESSA_Clinr.pdf.