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Methotrexate

Substrate Information
Inhibitor Information
Clinical Drug-drug Interactions

In Vitro Substrates

* denotes drugs that can potentially be used for in vivo (clinical) studies of the designated transporter

Transporter	Synonyms	Km (μM)	Cell System	Reference
ABCC3	MRP3	776	MRP3-expressing HEK293 vesicles	Zeng, 2000
SLC22A8	OAT3	10.9	OAT3-expressing oocytes	Cha, 2001
SLCO1B3	OATP1B3, OATP8	24.7	OATP1B3-expressing oocytes	Abe, 2001
SLCO1B3	OATP1B3, OATP8	39.4	MDCK-OATP1B3	Abe, 2001
SLCO1B1	OATP1B1, OATP-C, OATP2, LST-1	ND	OATP1B1-expressing oocytes	Abe, 2001
ABCC3	MRP3	620	MRP3-expressing HEK293 vesicles	Zeng, 2001
ABCC1	MRP1	2150	MRP1-expressing HEK293 vesicles	Zeng, 2001
ABCC4	MRP4	1300	MRP4-expressing Sf9 vesicles	van, 2002
ABCC4	MRP4	220	MRP4-expressing Sf9 vesicles	Chen, 2002
SLC22A11	OAT4	17.8	S2-OAT4	Takeda, 2002
SLC22A8	OAT3	21.1	S2-OAT3	Takeda, 2002
SLC22A6	OAT1	554	S2-OAT1	Takeda, 2002
ABCC3	MRP3	910	MRP1-expressing MCF7 vesicles	Paumi, 2003
ABCC1	MRP1	930	MRP1-expressing MCF7 vesicles	Paumi, 2003
ABCG2	BCRP, MXR	1340	BCRP-expressing HEK293 vesicles	Chen, 2003
ABCG2	BCRP, MXR	681	BCRP-expressing MCF7/MX vesicles	Volk, 2003
SLC22A8	OAT3	17.2	OAT3-expressing oocytes	Uwai, 2004
SLC22A6	OAT1	724	OAT1-expressing oocytes	Uwai, 2004
ABCC5	MRP5	1200	MRP5-expressing HEK293 vesicles	Wielinga, 2005
ABCC5	MRP5	1174	MRP5-expressing HEK293 vesicles	Pratt, 2006
SLCO1A2	OATP1A2, OATP-A	457	OATP1A2-expressing oocytes	Badagnani, 2006
ABCC4	MRP4	220	MRP4-expressing HEK293 vesicles	El-Sheikh, 2007
ABCC2	MRP2, cMOAT	480	MRP2-expressing HEK293 vesicles	El-Sheikh, 2007
ABCG2	BCRP, MXR	681	MDCK-transfected cells	Xia, 2007
ABCG2	BCRP, MXR	1410	BCRP-expressing HEK293 vesicles	Tiwari, 2009
SLCO2B1	OATP2B1, OATP-B	>300	OATP2B1-expressing oocytes	Visentin, 2012
SLC22A8	OAT3	76.6	HEK293-OAT3	Kurata, 2014

In Vitro Inhibitors

* denotes drugs that can potentially be used for in vivo (clinical) studies of the designated transporter

Transporter	Synonyms	Inhibitor	IC50 (μM)	Ki (μM)	Substrate used	Cell System	Reference
ABCC5	MRP5	Methotrexate	780		5-fluorodeoxyuridine monophosphate	MRP5-expressing HEK293 vesicles	Pratt, 2005
SLC22A8	OAT3	Methotrexate	92.2		Baricitinib	HEK-PEAK-OAT3	Posada, 2017
ABCC5	MRP5	Methotrexate		1059	Carboxydichlorofluorescein	MRP5-expressing HEK293 vesicles	Pratt, 2006
ABCC2	MRP2, cMOAT	Methotrexate	>133		Estradiol-17beta-glucuronide	Sf9 cell membrane vesicles	Morgan, 2013
ABCC3	MRP3	Methotrexate	>133		Estradiol-17beta-glucuronide	Sf9 cell membrane vesicles	Morgan, 2013
ABCC4	MRP4	Methotrexate	>133		Estradiol-17beta-glucuronide	Sf9 cell membrane vesicles	Morgan, 2013
ABCB11	BSEP	Methotrexate	>133		Taurocholate	Sf9 cell membrane vesicles	Morgan, 2013

Clinical Drug-Drug Interactions

DDI	Implicated Transporter*	Interacting Drug	Affected Drug	AUC	Cmax	CLR	CL/F	t1/2	Effect on PD	Reference	More Details
DDI	Implicated Transporter*	Interacting Drug	Affected Drug	Clinical PK Impact(fold change)					Effect on PD	Reference	More Details
1	OATs/BCRP	Isavuconazole	Methotrexate	0.97	0.89	ND	ND	ND	ND	Yamazaki, 2017	DDI 1

PK = pharmacokinetic
The transporters are implicated by in vitro data and/or studies in humans with genetic polymorphisms of the transporter
DDI = Drug Drug Interaction
PD = pharmacodynamic
ND = not determined
NS = not significant
N/A = information not available
Calculation of Fold Change: fold change in the presence of the interacting drug = (value with interacting drug)/(value without interacting drug)
fold change > 1: increase in pharmacokinetic value
fold change < 1: decrease in pharmacokinetic value