Details of the Drug-Related molecule(s) Interaction Atlas

General Information of Drug (ID: DMUAZWG)

• Drug Name: Leucovorin Drug Info
• Synonyms: 5-formyltetrahydrofolate; Citrovorum factor; Folinic acid

Indication

Disease Entry	ICD 11	Status	REF
Colon adenocarcinoma		Approved	[1]
Pervasive developmental disorder	6A00-6A0Z	Approved	[1]
Rectal adenocarcinoma	2B92	Approved	[1]
Rectum mucinous adenocarcinoma		Approved	[1]
Colon cancer	2B90.Z	Investigative	[1]
Colon mucinous adenocarcinoma		Investigative	[1]
Megaloblastic anemia		Investigative	[1]
Methotrexate toxicity		Investigative	[1]

• Therapeutic Class: Vitamins
• Cross-matching ID:
  PubChem CID: 135403648
  ChEBI ID: CHEBI:15640
  CAS Number: CAS 58-05-9
  TTD Drug ID: DMUAZWG
  VARIDT Drug ID: DR00238

Molecule-Related Drug Atlas

Drug(s) Transported By Multidrug resistance-associated protein 2 (ABCC2)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Doxorubicin	DMVP5YE	Acute myelogenous leukaemia	2A41	Approved	[5]
Methotrexate	DM2TEOL	Anterior urethra cancer		Approved	[6]
Folic Acid	DMEMBJC	Colorectal carcinoma		Approved	[7]
Fluorouracil	DMUM7HZ	Adenocarcinoma	2D40	Approved	[8]
Dinoprostone	DMTYOPD	Medical abortion	JA00.1Z	Approved	[9]
Cisplatin	DMRHGI9	Adenocarcinoma	2D40	Approved	[10]
Acetaminophen	DMUIE76	Allergic rhinitis	CA08.0	Approved	[11]
Sulfasalazine	DMICA9H	Irritable bowel syndrome	DD91.0	Approved	[12]
Etoposide	DMNH3PG	Acute myelogenous leukaemia	2A41	Approved	[13]
Oxaliplatin	DMQNWRD	Adenocarcinoma	2D40	Approved	[14]

Drug(s) Transported By Multidrug resistance-associated protein 3 (ABCC3)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Methotrexate	DM2TEOL	Anterior urethra cancer		Approved	[15]
Folic Acid	DMEMBJC	Colorectal carcinoma		Approved	[2]
Fluorouracil	DMUM7HZ	Adenocarcinoma	2D40	Approved	[16]
Etoposide	DMNH3PG	Acute myelogenous leukaemia	2A41	Approved	[17]
Ezetimibe	DM7A8TW	Atherosclerosis	BD40	Approved	[18]
Glibenclamide	DM8JXPZ	Diabetic complication	5A2Y	Approved	[19]
Morphine	DMRMS0L	Advanced cancer	2A00-2F9Z	Approved	[20]
Cefadroxil	DMMC345	Bacterial infection	1A00-1C4Z	Approved	[21]
Teniposide	DMLW57T	Acute lymphoblastic leukaemia	2A85	Approved	[22]
Fexofenadine	DM17ONX	Allergic rhinitis	CA08.0	Approved	[23]

Drug(s) Transported By Multidrug resistance-associated protein 4 (ABCC4)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Methotrexate	DM2TEOL	Anterior urethra cancer		Approved	[24]
Folic Acid	DMEMBJC	Colorectal carcinoma		Approved	[4]
Fluorouracil	DMUM7HZ	Adenocarcinoma	2D40	Approved	[16]
Dinoprostone	DMTYOPD	Medical abortion	JA00.1Z	Approved	[25]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[26]
Prasterone	DM67VKL	Chronic obstructive pulmonary disease	CA22	Approved	[27]
Irinotecan	DMP6SC2	Adenocarcinoma	2D40	Approved	[28]
Mercaptopurine	DMTM2IK	Acute lymphoblastic leukaemia	2A85	Approved	[29]
Glutathione	DMAHMT9	Human immunodeficiency virus infection	1C62	Approved	[30]
Ganciclovir	DM1MBYQ	Cytomegalovirus infection	1D82	Approved	[26]

Molecular Interaction Atlas of This Drug

Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
Multidrug resistance-associated protein 3 (ABCC3)	DTQ3ZHF	MRP3_HUMAN	Substrate	[2]
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[3]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[4]

References

• [1] Leucovorin FDA Label
• [2] Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res. 2001 Oct 1;61(19):7225-32.
• [3] Transport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17-(beta-D-glucuronide) by ABCG2: effects of acquired mutations at R482 on methotrexate transport. Cancer Res. 2003 Jul 15;63(14):4048-54.
• [4] Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4): MRP4 is a component of the methotrexate efflux system. Cancer Res. 2002 Jun 1;62(11):3144-50.
• [5] Involvement of the drug transporters p glycoprotein and multidrug resistance-associated protein Mrp2 in telithromycin transport. Antimicrob Agents Chemother. 2006 Jan;50(1):80-7.
• [6] Dose-dependent disposition of methotrexate in Abcc2 and Abcc3 gene knockout murine models. Drug Metab Dispos. 2011 Nov;39(11):2155-61.
• [7] Mammalian multidrug-resistance proteins (MRPs). Essays Biochem. 2011 Sep 7;50(1):179-207.
• [8] Enhancing chemosensitivity in oral squamous cell carcinoma by lentivirus vector-mediated RNA interference targeting EGFR and MRP2. Oncol Lett. 2016 Sep;12(3):2107-2114.
• [9] Multidrug resistance associated protein 2 mediates transport of prostaglandin E2. Liver Int. 2006 Apr;26(3):362-8.
• [10] Lentivirus-mediated RNAi silencing targeting ABCC2 increasing the sensitivity of a human nasopharyngeal carcinoma cell line against cisplatin. J Transl Med. 2008 Oct 4;6:55.
• [11] Effect of acetaminophen on expression and activity of rat liver multidrug resistance-associated protein 2 and P-glycoprotein. Biochem Pharmacol. 2004 Aug 15;68(4):791-8.
• [12] Small intestinal efflux mediated by MRP2 and BCRP shifts sulfasalazine intestinal permeability from high to low, enabling its colonic targeting. Am J Physiol Gastrointest Liver Physiol. 2009 Aug;297(2):G371-7.
• [13] Delineating the contribution of secretory transporters in the efflux of etoposide using Madin-Darby canine kidney (MDCK) cells overexpressing P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP1), and canalicular multispecific organic anion transporter (cMOAT). Drug Metab Dispos. 2002 Apr;30(4):457-63.
• [14] Multidrug Resistance-Associated Protein 2 (MRP2) Mediated Transport of Oxaliplatin-Derived Platinum in Membrane Vesicles. PLoS One. 2015 Jul 1;10(7):e0130727.
• [15] Multidrug resistance protein (MRP) 1 and MRP3 attenuate cytotoxic and transactivating effects of the cyclopentenone prostaglandin, 15-deoxy-Delta(12,14)prostaglandin J2 in MCF7 breast cancer cells. Biochemistry. 2003 May 13;42(18):5429-37.
• [16] ATP-binding cassette C transporters in human pancreatic carcinoma cell lines. Upregulation in 5-fluorouracil-resistant cells. Pancreatology. 2009;9(1-2):136-44.
• [17] Functional reconstitution of human ABCC3 into proteoliposomes reveals a transport mechanism with positive cooperativity. Biochemistry. 2009 May 26;48(20):4423-30.
• [18] Complex pharmacokinetic behavior of ezetimibe depends on abcc2, abcc3, and abcg2. Drug Metab Dispos. 2009 Aug;37(8):1698-702.
• [19] Transport of glyburide by placental ABC transporters: implications in fetal drug exposure. Placenta. 2006 Nov-Dec;27(11-12):1096-102.
• [20] Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch. 2007 Feb;453(5):661-73.
• [21] Oral availability of cefadroxil depends on ABCC3 and ABCC4. Drug Metab Dispos. 2012 Mar;40(3):515-21.
• [22] Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). J Biol Chem. 2001 Dec 7;276(49):46400-7.
• [23] Involvement of multiple efflux transporters in hepatic disposition of fexofenadine. Mol Pharmacol. 2008 May;73(5):1474-83.
• [24] Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/ABCC2- and MRP4/ABCC4-mediated methotrexate transport. J Pharmacol Exp Ther. 2007 Jan;320(1):229-35.
• [25] The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9244-9.
• [26] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [27] Steroid and bile acid conjugates are substrates of human multidrug-resistance protein (MRP) 4 (ATP-binding cassette C4). Biochem J. 2003 Apr 15;371(Pt 2):361-7.
• [28] P-glycoprotein, but not multidrug resistance protein 4, plays a role in the systemic clearance of irinotecan and SN-38 in mice. Drug Metab Lett. 2010 Dec;4(4):195-201.
• [29] Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia. Blood. 2009 Aug 13;114(7):1383-6.
• [30] Role of glutathione in the multidrug resistance protein 4 (MRP4/ABCC4)-mediated efflux of cAMP and resistance to purine analogues. Biochem J. 2002 Feb 1;361(Pt 3):497-503.