TABLE 4

CYP2C8-mediated reactions in vitro

Substrate	Metabolic Pathway	K_m	V_max	CL_int^{^a}	Test System	References
		µM	pmol/min/pmol (pmol/min/mg)	µl/min/pmol (µl/min/mg)
5-MeO-DIPT (Foxy)	N-deisopropylation	291	1.7	0.0058	rCYP2C8	Narimatsu et al., 2006
7-Epi-10-deacetyl-paclitaxel	Hydroxylation	18.0	3.038	0.17	rCYP2C8	Zhang et al., 2009a
7-Epi-cephalomannine	M-2 formation	2.6	1.882	0.72	rCYP2C8	Zhang et al., 2009a
7-Epi-paclitaxel	M-2 formation	1.4	1.409	1.0	rCYP2C8	Zhang et al., 2009b
8-prenylnaringenin	M2 formation	3.72	4.64	1.3	rCYP2C8	Guo et al., 2006
17α-ethinylestradiol	2-hydroxylation	12	0.064	0.0053	rCYP2C8	Wang et al., 2004
Acotiamide (Z-338)	Deisopropylation	152	(12.7)	(0.084)	rCYP2C8	Furuta et al., 2004
		318	(347)	(1.19)	HLM	Furuta et al., 2004
Alitretinoin (9-cis-retinoic acid)	4-hydroxylation	7	0.948	0.14	rCYP2C8	Marill et al., 2002
Aminophenazone (aminopyrine)	N-demethylation	5,300	188	0.035	rCYP2C8	Niwa et al., 1999
Amiodarone	N-deethylation	8.6	2.3	0.27	rCYP2C8	Ohyama et al., 2000
		5.22	(12.2)	(2.3)	rCYP2C8	Soyama et al., 2002
Amitriptyline	N-demethylation			0.072	rCYP2C8	Venkatakrishnan et al., 2001
Amodiaquine	N-deethylation	0.9-1.2	2.6-3.9	2.1-4.4	rCYP2C8	Li et al., 2002
		2.4	(1,462)	(610)	HLM	Li et al., 2002
		0.728	11.2	15	rCYP2C8	Walsky and Obach, 2004
		1.89	(1,480)	(780)	HLM	Walsky and Obach, 2004
		0.81	0.23	0.28	rCYP2C8	Parikh et al., 2007
		1	11	11	rCYP2C8	O'Donnell et al., 2007
		1.95	6.87^{^b}	3.5^{^b}	rCYP2C8	Baer et al., 2009
		1.6	(9,130)	(5,700)	HLM	Perloff et al., 2009
		3.0	5.7^{^b}	1.9^{^b}	rcCYP2C8	Kaspera et al., 2011
		3.33-5.17	(1,180-2,770)	(220-830)	HLM	Sjogren et al., 2012
		3.9-7.3	(791-861)	(120-200)	HLM	Yang et al., 2012
		1.9	(2,196)	(1,200)	HLM	Misaka et al., 2013
		1.8	(7.3)	(4.1)	HIM	Misaka et al., 2013
		58.8	3,234^{^c}	55^{^c}	Hep	Kosugi et al., 2014
		0.22-42.44	19.91-1,140^{^c}	24-95^{^c}	Hep	Li and Schlicht, 2014
Anastrozole	Hydroxylation	86.8	0.00005	<0.001	rCYP2C8	Kamdem et al., 2010
Arachidonic acid	Total oxidative metabolism	6.0	4.6^{^d}	0.77^{^d}	rCYP2C8	Barbosa-Sicard et al., 2005
	Epoxidation	71	0.078	0.0011	rCYP2C8	Lundblad et al., 2005
Atorvastatin (acid, parent)	p-hydroxylation	35.9	0.29	0.0081	rCYP2C8	Jacobsen et al., 2000b
Bedaquiline	N-demethylation	13.1			rCYP2C8	Liu et al., 2014
Buprenorphine	N-dealkylation	12.4	(176.3)	(14)	rCYP2C8	Picard et al., 2005
Buspirone	Total oxidative metabolism			0.073	rCYP2C8	Karlsson et al., 2013
BYZX	N-deethylation (M3)	62.1	0.099^{^e}	0.0016^{^e}	rCYP2C8	Yu et al., 2013a
BYZX M2	N-deethylation (M1)	143.2	(0.000370)	(<0.001)	rCYP2C8	Yu et al., 2013a
Caffeine	1-N-demethylation	920	0.014	<0.001	rCYP2C8	Kot and Daniel, 2008
	3-N-demethylation	200	0.016	<0.001	rCYP2C8	Kot and Daniel, 2008
	7-N-demethylation	3,560	0.172	<0.001	rCYP2C8	Kot and Daniel, 2008
	C-8-hydroxylation	3,370	0.319	<0.001	rCYP2C8	Kot and Daniel, 2008
Carbamazepine	10,11-epoxidation	757	0.669	<0.001	rCYP2C8	Cazali et al., 2003
Cephalomannine	6α-hydroxylation	41.3	5.267	0.13	rCYP2C8	Zhang et al., 2009a
Cerivastatin (acid, parent)	6-hydroxylation	23	0.22	0.0096	rcCYP2C8	Kaspera et al., 2010
	Demethylation	24	0.57	0.024	rcCYP2C8	Kaspera et al., 2010
Cerlapirdine	Demethylation	3.3	3.4	1.0	rCYP2C8	Tse et al., 2014
Chloroquine	N-deethylation	430	52.1	0.12	rCYP2C8	Kim et al., 2003
		111	8.33	0.075	rCYP2C8	Projean et al., 2003a
Cilostazol	OPC-13217 formation	33.8	0.30	0.089	rCYP2C8	Hiratsuka et al., 2007
Cisapride	4-hydroxylation	∼5.9	0.71	∼0.12	rCYP2C8	Desta et al., 2000
	N-dealkylation	∼0.91	0.29	∼0.32	rCYP2C8	Desta et al., 2000
	2-hydroxylation	5.80	0.0267	0.0046	rCYP2C8	Pearce et al., 2001
	4-hydroxylation	3.40	0.289	0.085	rCYP2C8	Pearce et al., 2001
	N-dealkylation	2.0	0.109	0.055	rCYP2C8	Pearce et al., 2001
(−)-Cisapride	4-hydroxylation	13.3	0.15	0.011	rCYP2C8	Desta et al., 2001
(+)-Cisapride	4-hydroxylation	12.6	0.24	0.019	rCYP2C8	Desta et al., 2001
Cyclosporine	Total oxidative metabolism			0.40	rCYP2C8	Karlsson et al., 2013
Dapsone	N-hydroxylation	58-75	0.440	0.0059-0.0076	rCYP2C8	Winter et al., 2000
Dibenzylfluorescein	O-debenzylation	1.0	0.4^{^d}	0.4^{^d}	n/a	Miller et al., 2000
		29.16	0.79	0.027	rCYP2C8	Ghosal et al., 2003
		1.9	(1.3)	(0.68)	THLE	Donato et al., 2004
Diclofenac	4′-hydroxylation	630	1.2^{^b}^,^{^d}	0.0019^{^b}^,^{^d}	rCYP2C8	Mancy et al., 1999
	5-hydroxylation	280	7^{^b}^,^{^d}	0.025^{^b}^,^{^d}	rCYP2C8	Mancy et al., 1999
DY-9760e	Imidazole oxidation (M8)	2.6	0.0732	0.028	rCYP2C8	Tachibana et al., 2005
	N-dealkylation (DY-9836)	15.2	0.0231	0.0015	rCYP2C8	Tachibana et al., 2005
	O-demethylation (M5)	3.1	0.0128	0.0041	rCYP2C8	Tachibana et al., 2005
	Phenyl hydroxylation (M3)	2.5	0.2955	0.12	rCYP2C8	Tachibana et al., 2005
Eicosapentaenoic acid	Total oxidative metabolism	5.4	6.2^{^d}	1.1^{^d}	rCYP2C8	Barbosa-Sicard et al., 2005
Estradiol-17β-glucuronide	2-hydroxylation	88	1.86	0.021	rCYP2C8	Delaforge et al., 2005
Ethanol	Acetaldehyde formation	8,300	(0.0043)	(<0.001)	rCYP2C8	Hamitouche et al., 2006
Eupatilin	4-O-demethylation	4.5	0.94	0.21	rCYP2C8	Lee et al., 2007
Felodipine	Total oxidative metabolism			1.1	rCYP2C8	Karlsson et al., 2013
Fenretidine	4′-hydroxylation	2.2	282^{^f}	130^{^f}	rCYP2C8	Illingworth et al., 2011
	4′-oxidation	5.0	30^{^f}	6.0^{^f}	rCYP2C8	Illingworth et al., 2011
R-Fluoxetine	N-demethylation	153.8	(6.08)	(0.040)	rcCYP2C8	Wang et al., 2014b
S-Fluoxetine	N-demethylation	195.0	(6.68)	(0.034)	rcCYP2C8	Wang et al., 2014b
Fluvastatin (acid, parent)	5-hydroxylation	2.8	0.13	0.046	rCYP2C8	Fischer et al., 1999
Gliclazide	6β-hydroxylation	984	0.63	<0.001	rCYP2C8	Elliot et al., 2007
	7β-hydroxylation	346	0.06	<0.001	rCYP2C8	Elliot et al., 2007
Glyburide (glibenclamide)	Total oxidative metabolism	10.2	0.9	0.09	rCYP2C8	Zharikova et al., 2009
		7.7	2.5	0.32	rCYP2C8	Zhou et al., 2010
				0.08	rCYP2C8	Varma et al., 2014
Halofantrine	N-debutylation	156	0.039	<0.001	rCYP2C8	Baune et al., 1999
Ibrolipim (NO-1886)	O-deethylation (M2)	28.4–53.9	0.0334–0.10	0.0012–0.0019	rCYP2C8	Morioka et al., 2002
R-Ibuprofen	2-hydroxylation	3.5–74			rCYP2C8	Hamman et al., 1997
		282	9.4	0.033	rCYP2C8	Chang et al., 2008
		341.3	4.92^{^e}	0.014^{^e}	rCYP2C8	Yu et al., 2013b
S-Ibuprofen	2-hydroxylation	292	5.4	0.018	rCYP2C8	Chang et al., 2008
		388.8	3.02^{^e}	0.0078^{^e}	rCYP2C8	Yu et al., 2013b
Imatinib	N-demethylation	1.4	0.408	0.29	rCYP2C8	Nebot et al., 2010
		4.28	4.07	0.95	rCYP2C8	Filppula et al., 2013a
		5	0.553	0.1	rCYP2C8	Khan et al., 2015
Isotretinoin (13-cis-retinoic acid)	4-hydroxylation	13.8	134.6^{^g}	9.8^{^g}	rCYP2C8	Rowbotham et al., 2010
L-775,606	Hydroxylation (M1)	42	0.62	0.015	rCYP2C8	Prueksaritanont et al., 2000
	N-dealkylation (M2)	64	0.03	<0.001	rCYP2C8	Prueksaritanont et al., 2000
Loperamide	N-demethylation	11.3	0.0052	<0.001	rCYP2C8	Kim et al., 2004
Magnolin	O-demethylation (M1)	17.7	1.9	0.11	rCYP2C8	Kim et al., 2011a
	O-demethylation (M2)	21.2	0.3021	0.014	rCYP2C8	Kim et al., 2011a
	Hydroxylation (M4)	29.7	0.7099	0.024	rCYP2C8	Kim et al., 2011a
Mavoglurant	Total oxidative metabolism	17.1	5.06	0.30	rCYP2C8	Walles et al., 2013
Mirodenafil	N-dealkylation (SK3541)	121	0.85	0.0070	rCYP2C8	Lee et al., 2008
Montelukast	36-hydroxylation (M6)	0.050	0.18	3.6	rCYP2C8	Filppula et al., 2011
		0.014	∼0.24	∼17	rCYP2C8	VandenBrink et al., 2011
		0.065	∼0.09	∼1	HLM	VandenBrink et al., 2011
		0.31	0.015	0.048	rCYP2C8	Oliveira Cardoso et al., 2015
	25-hydroxylation (M3)	0.33	0.002	0.006	rCYP2C8	Oliveira Cardoso et al., 2015
Morphine	N-demethylation	4,800	5.41	0.0011	rCYP2C8	Projean et al., 2003b
Nifedipine	Total oxidative metabolism			0.38	rCYP2C8	Karlsson et al., 2013
Nitidine chloride	Total oxidative metabolism	1.17	0.0705	0.060	rCYP2C8	Li et al., 2014b
R-Norverapamil	D-620 formation	56	5.3	0.095	rCYP2C8	Tracy et al., 1999
	PR-22 formation	38	29	0.76	rCYP2C8	Tracy et al., 1999
S-Norverapamil	D-620 formation	80	14	0.18	rCYP2C8	Tracy et al., 1999
	PR-22 formation	80	12	0.15	rCYP2C8	Tracy et al., 1999
Olanzapine	N-demethylation	30	1.370	0.046	rCYP2C8	Korprasertthaworn et al., 2015
Omeprazole	5-hydroxylation	300	3.3	0.011	rCYP2C8	Karam et al., 1996
Paclitaxel	6α-hydroxylation	5.4	30	5.6	rCYP2C8	Rahman et al., 1994
		4.0	(870)	(220)	HLM	Rahman et al., 1994
		15	0.12	0.0080	HLM	Monsarrat et al., 1997
		17			HLM	Ando et al., 1998
		26			HLM	Desai et al., 1998
		34.8	(1632)	(47)	HLM	Fischer et al., 1998
		4.9	1.14	0.23	rCYP2C8	Masimirembwa et al., 1999
		6	(234)	(39)	rCYP2C8	Ong et al., 2000
		12.2	(142)	(12)	HLM	Ong et al., 2000
		2.85	5.667	2.0	rCYP2C8	Ohyama et al., 2000
		2.58–4.55	0.224–0.583	0.070–0.19	HLM	Ohyama et al., 2000
		6.8	3.0^{^d}	0.44^{^d}	rCYP2C8	Yamazaki et al., 2000
		15	0.8	0.053	rCYP2C8	Dai et al., 2001
		4.3	(147)	(34)	rCYP2C8	Fujino et al., 2001
		27.4	(359)	(13)	HLM	Fujino et al., 2001
		16.2	29.8	1.8	rCYP2C8	Soyama et al., 2001
		15	1.950	0.13	HLM	Cresteil et al., 2002
		9.3	(60.9)	(6.8)	HLM	Václavíková et al., 2003
		13.3	(109.1)	(8.2)	HLM	Donato et al., 2004
		16.3	(81.0)	(5.0)	THLE	Donato et al., 2004
		7.50	(70.2)	(9.4)	HLM	Polasek et al., 2004
		8.3	1.718	0.21	rCYP2C8	Zhang et al., 2009b
		18.3	(250)	(14)	HLM	Zhang et al., 2009b
		4.17	2.4	0.58	rCYP2C8	Gao et al., 2010
		2.33	4.05	1.7	rCYP2C8	Hanioka et al., 2010
		3.7	0.29^{^b}	0.078^{^b}	rcCYP2C8	Kaspera et al., 2011
		2.58	3.53	1.4	rCYP2C8	Wattanachai et al., 2011
		7.08	(137)	(19)	HLM	Wattanachai et al., 2011
		8.65	69.83	8.1	rCYP2C8	Yu et al., 2013b
		5.2	(222.1)	(43)	HLM	Wang et al., 2014a
		5.41–15.9	(52.6–230)	(3.3–26)	HLM	Kudo et al., 2015
Pafuramidine maleate (DB289)	O-demethylation (M1)	2.6	0.12	0.046	rCYP2C8	Wang et al., 2006
Perospirone	Total oxidative metabolism	1.09	1.93	1.8	rCYP2C8	Kitamura et al., 2005
Perphenazine	N-dealkylation	28	1.35	0.048	rCYP2C8	Olesen and Linnet, 2000
Phenazone (antipyrine)	N-demethylation	30,400	(156.4)	(0.0051)	rCYP2C8	Engel el al., 1996
	3-hydroxylation	22,000	(43.9)	(0.0020)	rCYP2C8	Engel el al., 1996
	4-hydroxylation	61,000	(140.9)	(0.0023)	rCYP2C8	Engel el al., 1996
Phenprocoumon	S-4′-hydroxylation	3.78	0.027	0.0071	rCYP2C8	Ufer et al., 2004
Pioglitazone	M-IV formation	10.2	9.2	0.91	rCYP2C8	Tornio et al., 2008b
		9.8	(640)	(65)	HLM	Tornio et al., 2008b
		29.5	1.702	0.058	rCYP2C8	Muschler et al., 2009
R483	Hydroxylation (M1)	1.4	(1,000)	(700)	n/a	Bogman et al., 2010
Repaglinide	Total oxidative metabolism	2.8	4.9	1.8	rCYP2C8	Kajosaari et al., 2005a
	M1 formation	25	0.08	0.003	rCYP2C8	Säll et al., 2012
	M4 formation	5.7	0.35	0.061	rCYP2C8	Säll et al., 2012
	M4 formation	9.0	(130)	(14)	HLM	Säll et al., 2012
	M4 formation	28	13^{^c}	0.46^{^c}	Hep	Säll et al., 2012
	M4 formation	13	(18)	(1.4)	S9	Säll et al., 2012
		12.01	15.69^{^e}	1.3^{^e}	rCYP2C8	Yu et al., 2013b
Rosiglitazone	p-hydroxylation	44	(2,900)	(66)	rCYP2C8	Baldwin et al., 1999
		4.3–7.7	(550–883)	(93–130)	HLM	Baldwin et al., 1999
	N-demethylation	10	(2,430)	(240)	rCYP2C8	Baldwin et al., 1999
	p-hydroxylation	4.0	0.42^{^b}	0.11^{^b}	rcCYP2C8	Kaspera et al., 2011
	N-demethylation	2.9	0.38^{^b}	0.13^{^b}	rcCYP2C8	Kaspera et al., 2011
Selegiline	Demethylation	82	3	0.04	rCYP2C8	Hidestrand et al., 2001
	Levomethamphetamine formation	630	7	0.01	rCYP2C8	Hidestrand et al., 2001
Seratrodast	4′-hydroxylation	28.2	0.1438	0.0051	rCYP2C8	Kumar et al., 1997
	5-methylhydroxylation	32.9	0.4983	0.015	rCYP2C8	Kumar et al., 1997
Sildenafil	Total oxidative metabolism			0.055	rCYP2C8	Karlsson et al., 2013
Simvastatin acid	M1 formation	88	2,800	32	rCYP2C8	Prueksaritanont et al., 2003
	M2 formation	36	850	24	rCYP2C8	Prueksaritanont et al., 2003
	M3 formation	16	600	38	rCYP2C8	Prueksaritanont et al., 2003
T-5	N-oxidation	1.6	0.22	0.14	rCYP2C8	Li et al., 2014a
Tacrolimus	Total oxidative metabolism			0.19	rCYP2C8	Karlsson et al., 2013
Tanshinol borneol ester	M3 formation	45.2	4.28^{^h}	0.095^{^h}	rCYP2C8	Liu et al., 2010b
Terbinafine	Deamination	24.8	0.512	0.021	rCYP2C8	Vickers et al., 1999
	N-demethylation	13.6	2.06	0.15	rCYP2C8	Vickers et al., 1999
	Side chain oxidation	26.4	0.825	0.031	rCYP2C8	Vickers et al., 1999
	Total oxidative metabolism	15.3	4.47	0.29	rCYP2C8	Vickers et al., 1999
R-Tofisopam	M3 formation	52	0.43	0.0083	rCYP2C8	Cameron et al., 2007
Tolbutamide	Hydroxylation	650.5			rCYP2C8	Veronese et al., 1993
		531	0.39	<0.001	rCYP2C8	Rettie et al., 1994
		1,160	(10.2)	(0.0088)	rCYP2C8	Pang et al., 2012
Torsemide (torasemide)	Methyl hydroxylation	184	1.8	0.0098	rCYP2C8	Miners et al., 2000
		170	(35)	(0.21)	rCYP2C8	Ong et al., 2000
Tozasertib (MK 0457, VX6, VX 680)	N-demethylation	64	129	2.0	rCYP2C8	Ballard et al., 2007
Tretinoin (all-trans-retinoic acid)	4-hydroxylation	6.1	0.18	0.030	rCYP2C8	Nadin and Murray, 1999
	4-hydroxylation	50	1.211	0.024	rCYP2C8	Marill et al., 2000
	18-hydroxylation	17	0.033	0.0019	rCYP2C8	Marill et al., 2000
	5,6-epoxy metabolite formation	130	0.450	0.0035	rCYP2C8	Marill et al., 2000
	4-hydroxylation	13.4	4.8	0.36	rCYP2C8	Thatcher et al., 2010
Troglitazone	Quinone formation	2.7	4.2^{^d}	1.6^{^d}	rCYP2C8	Yamazaki et al., 1999b
Verapamil	O-demethylation	48.4	(13)	(0.27)	rCYP2C8	Busse et al., 1995
	Total oxidative metabolism			0.39	rCYP2C8	Karlsson et al., 2013
R-Verapamil	D-617 formation	127	8.0	0.063	rCYP2C8	Tracy et al., 1999
	Norverapamil formation	127	6.9	0.054	rCYP2C8	Tracy et al., 1999
	PR-22 formation	33	2.2	0.067	rCYP2C8	Tracy et al., 1999
S-Verapamil	D-617 formation	185	8.0	0.043	rCYP2C8	Tracy et al., 1999
	Norverapamil formation	154	15	0.097	rCYP2C8	Tracy et al., 1999
	PR-22 formation	141	1.6	0.011	rCYP2C8	Tracy et al., 1999
Vidupiprant (AMG 853)	t-butyl hydroxylation (M2)	1.21	0.031	0.026	rCYP2C8	Foti et al., 2012
	Cyclopropyl hydroxylation (M3)	49.1	0.250	0.0051	rCYP2C8	Foti et al., 2012
Vitamin A (retinol)	4-hydroxylation	71	1.73	0.024	rcCYP2C8	Leo et al., 1989
Zopiclone	N-demethylation	71	2.5	0.035	rCYP2C8	Becquemont et al., 1999
	N-oxidation	59	1.0	0.017	rCYP2C8	Becquemont et al., 1999

5-MeO-DIPT, 5-methoxy-N,N-diisopropyltryptamine; BYZX, [(E)-2-(4-((diethylamino)methyl)benzylidene)-5,6-dimethoxy-2,3-dihydroinden-one]; CL_int, intrinsic clearance; Hep, hepatocytes; HIM, human intestinal microsomes; HLM, human liver microsomes; K_m, Michaelis-Menten constant; n/a, not available; rCYP2C8, recombinant CYP2C8; rcCYP2C8, reconstituted CYP2C8; S9, S9 fraction; THLE, immortalized human liver epithelial cells; V_max, maximal velocity.
↵^a Calculated as V_max/K_m.
↵^b k_cat reported instead of V_max, CL_int calculated as k_cat/K_m.
↵^c V_max as pmol/min/10⁶ cells, CL_int as pmol/min/10⁶ cells/µM.
↵^d V_max as 1/min, CL_int as 1/min/µM.
↵^e V_max as arbitrary unit (AU), CL_int as AU/µM.
↵^f V_max as unit/min, CL_int as unit/min/µM.
↵^g V_max as counts/s/s, CL_int as counts/s/s/µM.
↵^h V_max as AUC⋅min/nmol, CL_int as AUC⋅min/nmol/µM.