TABLE 8

Metabolism-dependent CYP2C8 inhibitors in vitro

Inhibitor	Therapeutic Use and/or Drug Class	Mode of Inhibition	Preinc. IC₅₀^{^a}	IC₅₀ Shift^{^b}	K_I	k_inact	Test System	Marker Reaction^{^c}	References
			µM	ratio	µM	1/min
17α-Ethinylestradiol	Contraceptive, hormone derivative		8.3	1.9			HLM	Pacli	Chang et al., 2009
Amiodarone	Antiarrhythmic				1.5	0.079	rCYP2C8	Pacli	Polasek et al., 2004
					51.2	0.029	HLM	Pacli	Polasek et al., 2004
Bosutinib	Anticancer, PKI		16.9	2.6	54.8	0.018	HLM	Amo	Filppula et al., 2014
Clopidogrel acyl 1-β-D-glucuronide	Drug metabolite		12.0	4.7	9.9	0.047	HLM	Amo	Tornio et al., 2014
Desethylamiodarone	Drug metabolite		0.67	3.3	4.4	0.009	HLM	Amo	Obach et al., 2007
Demethyldabrafenib	Drug metabolite		30^{^a}	1.6			HLM	Rosi	Lawrence et al., 2014
Fluoxetine	Antidepressant, SSRI	Quasi-irreversible			294	0.083	rCYP2C8	Pacli	Polasek et al., 2004
Gemfibrozil 1-O-β glucuronide	Drug metabolite	Irreversible	1.8	13.3	20-52	0.21	HLM	Pacli	Ogilvie et al., 2006
					4.51	0.106	Hep	n/a	Negishi et al., 2007
					29	0.072	rCYP2C8	Amo	Baer et al., 2009
			0.46	98			HLM	Amo	Perloff et al., 2009
			3.0				HLM	Monte	Karonen et al., 2010
			4.5				HLM	Monte-4	Karonen et al., 2010
					0.26	0.015	HLM	Amo	Teng et al., 2010
			1.4	16			HLM	Amo	Jenkins et al., 2011
					10.1	0.041	HLM	Amo	VandenBrink et al., 2011
					21.3	0.050	HLM	Monte	VandenBrink et al., 2011
					35	0.022	HLM	Pacli	VandenBrink et al., 2011
					33.6	0.082	HLM	Pio	VandenBrink et al., 2011
					18.4	0.035	HLM	Repa	VandenBrink et al., 2011
					48.5	0.071	HLM	Rosi	VandenBrink et al., 2011
					10.34–25.4	0.104–0.25	HLM	Amo	Korzekwa et al., 2014
Gemfibrozil d₆-1-O-β glucuronide	Drug metabolite, Deuterated				29	0.033	rCYP2C8	Amo	Baer et al., 2009
Isoniazid	Antituberculosis	Quasi-irreversible			374	0.042	rCYP2C8	Pacli	Polasek et al., 2004
					170	0.012	HLM	Pacli	Polasek et al., 2004
Lu AA34893 carbamoyl glucuronide	Drug Metabolite		8.5	8.4			HLM	n/a	Kazmi et al., 2010
O-methylgemfibrozil acyl-β-d-glucuronide	Gemfibrozil Acyl-β-d-glucuronide Analog		17	3.2			HLM	Amo	Jenkins et al., 2011
Nortriptyline	Antidepressant, TCA	Quasi-irreversible			49.9	0.036	rCYP2C8	Pacli	Polasek et al., 2004
Phenelzine	Antidepressant, MAOI				1.2	0.243	rCYP2C8	Pacli	Polasek et al., 2004
					54.3	0.17	HLM	Pacli	Polasek et al., 2004
Raloxifene	Antiosteoperotic, SERM			>2	0.26	0.1	rCYP2C8	Pacli	VandenBrink et al., 2012
Thujopsene	Sesquiterpene		29.8	3.3			HLM	Amo	Jeong et al., 2014
Toremifene	Anticancer, SERM		5.0	1.9			HLM	Pacli	Kim et al., 2011b
Verapamil	Antihypertensive, CCB	Quasi-irreversible			17.5	0.065	rCYP2C8	Pacli	Polasek et al., 2004

CCB, calcium channel blocker; Hep, hepatocytes: HLM, human liver microsomes; IC₅₀, inhibitor concentration supporting half of the maximal inhibition; K_I, inactivation constant; k_inact, maximal rate of inactivation; MAOI, monoamine oxidase inhibitor; n/a, not available; PKI, protein kinase inhibitor; rCYP2C8, recombinant CYP2C8, SERM, selective estrogen receptor modulator; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
↵^a Preinc. IC₅₀ depicts IC₅₀ after preincubation of inhibitor for 30 min with NADPH before addition of substrate, except in the case of demethyldabrafenib where the preincubation time was 20 min.
↵^b IC₅₀ shift = reversible IC₅₀/preinc. IC₅₀. An IC₅₀ shift ≥1.5-fold is indicative of metabolism-dependent inhibition.
↵^c Amo, amodiaquine N-deethylation; Monte, montelukast 36-hydroxylation; Monte-4, formation of montelukast M4; Pacli, paclitaxel 6α-hydroxylation; Pio; pioglitazone hydroxylation (M-IV); Repa, repaglinide 3′-hydroxylation; Rosi, rosiglitazone N-demethylation.