Details of the Drug

General Information of Drug (ID: DMMX2E6)

• Drug Name: Pemetrexed
• Synonyms: Alimta; LYA; LY 231514; LY231514; Alimta (TN); LY 231,514; LY-2315; LY-231514; Pemetrexed (INN); Pemetrexed [INN:BAN]; LY-231,514; N-(4-(2-(2-Amino-3,4-dihydro-4-oxo-7H-pyrrolo(2,3-d)pyrimdin-5-yl)ethyl)benzoyl)glutamic acid; N-{4-[2-(2-amino-4-oxo-4,7-dihydro-1h-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-d-glutamic acid; (2R)-2-[[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioic acid; (2S)-2-[[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioic acid; 2-[[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioic acid; 2-{4-[2-(2-AMINO-4-OXO-4,7-DIHYDRO-3H-PYRROLO[2,3-D]PYRIMIDIN-5-YL)-ETHYL]-BENZOYLAMINO}-PENTANEDIOIC ACID

Indication

Disease Entry	ICD 11	Status	REF
Central nervous system lymphoma	2B33.5	Approved	[1]
Epithelioid mesothelioma	2F10	Approved	[1]
Lung cancer	2C25.0	Approved	[1]
Malignant pleural mesothelioma	2C26.0	Approved	[2]
Non-small-cell lung cancer	2C25.Y	Approved	[1]
Sarcomatoid mesothelioma	N.A.	Approved	[1]
Small-cell lung cancer	2C25.Y	Approved	[1]
Lung neoplasm	N.A.	Investigative	[1]

• Therapeutic Class: Anticancer Agents
• Affected Organisms: Humans and other mammals
• ATC Code:
  L01BA04: Pemetrexed
  L01BA: Folic acid analogues
  L01B: ANTIMETABOLITES
  L01: ANTINEOPLASTIC AGENTS
  L: ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 1:
  Molecular Weight (mw); 427.4
  Logarithm of the Partition Coefficient (xlogp); 0.2
  Rotatable Bond Count (rotbonds); 9
  Hydrogen Bond Donor Count (hbonddonor); 6
  Hydrogen Bond Acceptor Count (hbondacc); 7
• ADMET Property:
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3: high solubility and low permeability [3]
  Clearance: The drug present in the plasma can be removed from the body at the rate of 1.3 mL/min/kg [4]
  Elimination: 80% of drug is excreted from urine in the unchanged form [3]
  Half-life: The concentration or amount of drug in body reduced by one-half in 3.5 hours [4]
  Metabolism: The drug is metabolized via the cytochrome P450 Enzymes []
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 1.377 micromolar/kg/day [5]
  Unbound Fraction: The unbound fraction of drug in plasma is 0.19% [4]
  Vd: The volume of distribution (Vd) of drug is 16.1 L []
  Water Solubility: The ability of drug to dissolve in water is measured as 90 mg/mL [3]
• Chemical Identifiers:
  Formula: C20H21N5O6
  IUPAC Name: (2S)-2-[[4-[2-(2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioic acid
  Canonical SMILES: C1=CC(=CC=C1CCC2=CNC3=C2C(=O)NC(=N3)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O
  InChI: InChI=1S/C20H21N5O6/c21-20-24-16-15(18(29)25-20)12(9-22-16)6-3-10-1-4-11(5-2-10)17(28)23-13(19(30)31)7-8-14(26)27/h1-2,4-5,9,13H,3,6-8H2,(H,23,28)(H,26,27)(H,30,31)(H4,21,22,24,25,29)/t13-/m0/s1
  InChIKey: WBXPDJSOTKVWSJ-ZDUSSCGKSA-N
• Cross-matching ID:
  PubChem CID: 135410875
  ChEBI ID: CHEMBL225072
  CAS Number: 137281-23-3
  UNII: 04Q9AIZ7NO
  DrugBank ID: DB00642
  TTD ID: D0Y4GO
  VARIDT ID: DR00318
• Drug-Molecule Activity Atlas (DMA)NEW: Click to Jump to the Detailed DMA Information of This Drug
• Repurposed Drugs (RPD): Click to Jump to the Detailed RPD Information of This Drug

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Candida Thymidylate synthase (Candi TMP1)	TTU6BFZ	TYSY_CANAL	Inhibitor	[6]

Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
Folate transporter 1 (SLC19A1)	DTOSN46	S19A1_HUMAN	Substrate	[7]
Proton-coupled folate transporter (SLC46A1)	DTDJEMI	PCFT_HUMAN	Substrate	[8]
Multidrug resistance-associated protein 5 (ABCC5)	DTYVM24	MRP5_HUMAN	Substrate	[9]
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[10]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[11]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[12]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
ATP-binding cassette sub-family C member 11 (ABCC11)	OTVHL7OR	MRP8_HUMAN	Drug Response	[13]
ATP-binding cassette sub-family C member 5 (ABCC5)	OT34G4US	MRP5_HUMAN	Drug Response	[14]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Gene/Protein Processing	[15]
Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial (MTHFD2)	OT1LQSGX	MTDC_HUMAN	Drug Response	[16]
CASP8 and FADD-like apoptosis regulator (CFLAR)	OTX14BAS	CFLAR_HUMAN	Drug Response	[17]
DNA excision repair protein ERCC-1 (ERCC1)	OTNPYQHI	ERCC1_HUMAN	Gene/Protein Processing	[18]
Folylpolyglutamate synthase, mitochondrial (FPGS)	OTW3F1ZE	FOLC_HUMAN	Drug Response	[19]
Reduced folate transporter (SLC19A1)	OTWB0BTO	S19A1_HUMAN	Drug Response	[20]
Splicing factor 45 (RBM17)	OT9ROJCL	SPF45_HUMAN	Drug Response	[21]
Thymidine phosphorylase	OT6BQTMR	TYPH_HUMAN	Drug Response	[19]

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Pemetrexed (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Framycetin	DMF8DNE	Moderate	Decreased renal excretion of Pemetrexed caused by Framycetin mediated nephrotoxicity.	Alcoholic liver disease [DB94]	[22]
Inotersen	DMJ93CT	Moderate	Decreased renal excretion of Pemetrexed caused by Inotersen mediated nephrotoxicity.	Amyloidosis [5D00]	[22]
Roflumilast	DMPGHY8	Moderate	Additive immunosuppressive effects by the combination of Pemetrexed and Roflumilast.	Asthma [CA23]	[23]
Kanamycin	DM2DMPO	Moderate	Decreased renal excretion of Pemetrexed caused by Kanamycin mediated nephrotoxicity.	Bacterial infection [1A00-1C4Z]	[22]
Streptomycin	DME1LQN	Moderate	Decreased renal excretion of Pemetrexed caused by Streptomycin mediated nephrotoxicity.	Bacterial infection [1A00-1C4Z]	[22]
Gentamicin	DMKINJO	Moderate	Decreased renal excretion of Pemetrexed caused by Gentamicin mediated nephrotoxicity.	Bacterial infection [1A00-1C4Z]	[22]
Netilmicin	DMRD1QK	Moderate	Decreased renal excretion of Pemetrexed caused by Netilmicin mediated nephrotoxicity.	Bacterial infection [1A00-1C4Z]	[22]
Tobramycin	DMUI0CH	Moderate	Decreased renal excretion of Pemetrexed caused by Tobramycin mediated nephrotoxicity.	Bacterial infection [1A00-1C4Z]	[22]
Etidronic acid	DM1XHYJ	Moderate	Decreased renal excretion of Pemetrexed caused by Etidronic acid mediated nephrotoxicity.	Bone paget disease [FB85]	[22]
Methoxyflurane	DML0RAE	Moderate	Decreased renal excretion of Pemetrexed caused by Methoxyflurane mediated nephrotoxicity.	Corneal disease [9A76-9A78]	[22]
Pentamidine	DMHZJCG	Moderate	Decreased renal excretion of Pemetrexed caused by Pentamidine mediated nephrotoxicity.	Fungal infection [1F29-1F2F]	[22]
Amphotericin B	DMTAJQE	Moderate	Decreased renal excretion of Pemetrexed caused by Amphotericin B mediated nephrotoxicity.	Fungal infection [1F29-1F2F]	[22]
Teriflunomide	DMQ2FKJ	Major	Additive immunosuppressive effects by the combination of Pemetrexed and Teriflunomide.	Hyper-lipoproteinaemia [5C80]	[24]
Givosiran	DM5PFIJ	Moderate	Decreased renal excretion of Pemetrexed caused by Givosiran mediated nephrotoxicity.	Inborn porphyrin/heme metabolism error [5C58]	[22]
Balsalazide	DM7I1T9	Moderate	Decreased renal excretion of Pemetrexed caused by Balsalazide mediated nephrotoxicity.	Indeterminate colitis [DD72]	[22]
Denosumab	DMNI0KO	Moderate	Additive myelosuppressive effects by the combination of Pemetrexed and Denosumab.	Low bone mass disorder [FB83]	[25]
Moxetumomab pasudotox	DMN63DZ	Moderate	Decreased renal excretion of Pemetrexed caused by Moxetumomab pasudotox mediated nephrotoxicity.	Mature B-cell leukaemia [2A82]	[22]
Exjade	DMHPRWG	Moderate	Decreased renal excretion of Pemetrexed caused by Exjade mediated nephrotoxicity.	Mineral absorption/transport disorder [5C64]	[22]
Gallium nitrate	DMF9O6B	Moderate	Decreased renal excretion of Pemetrexed caused by Gallium nitrate mediated nephrotoxicity.	Mineral excesses [5B91]	[22]
Thalidomide	DM70BU5	Major	Additive thrombogenic effects by the combination of Pemetrexed and Thalidomide.	Multiple myeloma [2A83]	[26]
Tecfidera	DM2OVDT	Moderate	Additive immunosuppressive effects by the combination of Pemetrexed and Tecfidera.	Multiple sclerosis [8A40]	[27]
Siponimod	DM2R86O	Major	Additive immunosuppressive effects by the combination of Pemetrexed and Siponimod.	Multiple sclerosis [8A40]	[28]
Fingolimod	DM5JVAN	Major	Additive immunosuppressive effects by the combination of Pemetrexed and Fingolimod.	Multiple sclerosis [8A40]	[29]
Ocrelizumab	DMEZ2KH	Moderate	Additive immunosuppressive effects by the combination of Pemetrexed and Ocrelizumab.	Multiple sclerosis [8A40]	[30]
Ozanimod	DMT6AM2	Major	Additive immunosuppressive effects by the combination of Pemetrexed and Ozanimod.	Multiple sclerosis [8A40]	[23]
Omacetaxine mepesuccinate	DMPU2WX	Moderate	Additive myelosuppressive effects by the combination of Pemetrexed and Omacetaxine mepesuccinate.	Myeloproliferative neoplasm [2A20]	[31]
Temsirolimus	DMS104F	Moderate	Decreased renal excretion of Pemetrexed caused by Temsirolimus mediated nephrotoxicity.	Renal cell carcinoma [2C90]	[22]
Colistimethate	DMZ9BMU	Moderate	Decreased renal excretion of Pemetrexed caused by Colistimethate mediated nephrotoxicity.	Respiratory infection [CA07-CA4Z]	[22]
Canakinumab	DM8HLO5	Moderate	Additive immunosuppressive effects by the combination of Pemetrexed and Canakinumab.	Rheumatoid arthritis [FA20]	[32]
Rilonacept	DMGLUQS	Moderate	Additive immunosuppressive effects by the combination of Pemetrexed and Rilonacept.	Rheumatoid arthritis [FA20]	[32]
Golimumab	DMHZV7X	Major	Additive immunosuppressive effects by the combination of Pemetrexed and Golimumab.	Rheumatoid arthritis [FA20]	[33]
Sulfasalazine	DMICA9H	Moderate	Decreased renal excretion of Pemetrexed caused by Sulfasalazine mediated nephrotoxicity.	Rheumatoid arthritis [FA20]	[22]
Leflunomide	DMR8ONJ	Major	Additive immunosuppressive effects by the combination of Pemetrexed and Leflunomide.	Rheumatoid arthritis [FA20]	[24]
Anthrax vaccine	DM9GSWY	Moderate	Antagonize the effect of Pemetrexed when combined with Anthrax vaccine.	Sepsis [1G40-1G41]	[34]
Telavancin	DM58VQX	Moderate	Decreased renal excretion of Pemetrexed caused by Telavancin mediated nephrotoxicity.	Staphylococcal/streptococcal disease [1B5Y]	[22]
Sirolimus	DMGW1ID	Moderate	Decreased renal excretion of Pemetrexed caused by Sirolimus mediated nephrotoxicity.	Transplant rejection [NE84]	[22]
Azathioprine	DMMZSXQ	Moderate	Additive immunosuppressive effects by the combination of Pemetrexed and Azathioprine.	Transplant rejection [NE84]	[28]
Tacrolimus	DMZ7XNQ	Moderate	Decreased renal excretion of Pemetrexed caused by Tacrolimus mediated nephrotoxicity.	Transplant rejection [NE84]	[22]
Olsalazine	DMZW9HA	Moderate	Decreased renal excretion of Pemetrexed caused by Olsalazine mediated nephrotoxicity.	Ulcerative colitis [DD71]	[22]
Plazomicin	DMKMBES	Moderate	Decreased renal excretion of Pemetrexed caused by Plazomicin mediated nephrotoxicity.	Urinary tract infection [GC08]	[22]
Ganciclovir	DM1MBYQ	Moderate	Additive myelosuppressive effects by the combination of Pemetrexed and Ganciclovir.	Virus infection [1A24-1D9Z]	[28]
Valganciclovir	DMS2IUH	Moderate	Additive myelosuppressive effects by the combination of Pemetrexed and Valganciclovir.	Virus infection [1A24-1D9Z]	[28]

References

• [1] Pemetrexed FDA Label
• [2] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6837).
• [3] BDDCS applied to over 900 drugs
• [4] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [5] Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
• [6] Updated clinical information on multitargeted antifolates in lung cancer. Clin Lung Cancer. 2009 Mar;10 Suppl 1:S35-40.
• [7] Biology of the major facilitative folate transporters SLC19A1 and SLC46A1. Curr Top Membr. 2014;73:175-204.
• [8] The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier. Mol Pharmacol. 2008 Sep;74(3):854-62.
• [9] Kinetic validation of the use of carboxydichlorofluorescein as a drug surrogate for MRP5-mediated transport. Eur J Pharm Sci. 2006 Apr;27(5):524-32.
• [10] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [11] Substrate- and pH-specific antifolate transport mediated by organic anion-transporting polypeptide 2B1 (OATP2B1-SLCO2B1). Mol Pharmacol. 2012 Feb;81(2):134-42.
• [12] pH-Dependent transport of pemetrexed by breast cancer resistance protein. Drug Metab Dispos. 2011 Sep;39(9):1478-85.
• [13] ABCC11/MRP8 confers pemetrexed resistance in lung cancer. Cancer Sci. 2010 Nov;101(11):2404-10.
• [14] The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites. Mol Cancer Ther. 2005 May;4(5):855-63.
• [15] Xanthohumol inhibits non-small cell lung cancer by activating PUMA-mediated apoptosis. Toxicology. 2022 Mar 30;470:153141. doi: 10.1016/j.tox.2022.153141. Epub 2022 Mar 5.
• [16] KRAS mutation status is associated with enhanced dependency on folate metabolism pathways in non-small cell lung cancer cells. Mol Cancer Ther. 2014 Jun;13(6):1611-24. doi: 10.1158/1535-7163.MCT-13-0649. Epub 2014 Mar 31.
• [17] Death receptor 5 and cellular FLICE-inhibitory protein regulate pemetrexed-induced apoptosis in human lung cancer cells. Eur J Cancer. 2011 Nov;47(16):2471-8. doi: 10.1016/j.ejca.2011.06.003. Epub 2011 Jul 2.
• [18] Pemetrexed downregulates ERCC1 expression and enhances cytotoxicity effected by resveratrol in human nonsmall cell lung cancer cells. Naunyn Schmiedebergs Arch Pharmacol. 2013 Dec;386(12):1047-59. doi: 10.1007/s00210-013-0905-9. Epub 2013 Aug 3.
• [19] A randomized, double-blind, phase II study of two doses of pemetrexed as first-line chemotherapy for advanced breast cancer. Clin Cancer Res. 2007 Jun 15;13(12):3652-9. doi: 10.1158/1078-0432.CCR-06-2377.
• [20] The inverse relationship between reduced folate carrier function and pemetrexed activity in a human colon cancer cell line. Mol Cancer Ther. 2006 Feb;5(2):438-49. doi: 10.1158/1535-7163.MCT-05-0243.
• [21] Human splicing factor SPF45 (RBM17) confers broad multidrug resistance to anticancer drugs when overexpressed--a phenotype partially reversed by selective estrogen receptor modulators. Cancer Res. 2005 Aug 1;65(15):6593-600. doi: 10.1158/0008-5472.CAN-03-3675.
• [22] Product Information. Alimta (pemetrexed). Lilly, Eli and Company, Indianapolis, IN.
• [23] Cerner Multum, Inc. "UK Summary of Product Characteristics.".
• [24] Product Information. Arava (leflunomide). Hoechst Marion-Roussel Inc, Kansas City, MO.
• [25] Product Information. Prolia (denosumab). Amgen USA, Thousand Oaks, CA.
• [26] Bennett CL, Nebeker JR, Samore MH, et al "The Research on Adverse Drug Events and Reports (RADAR) project." JAMA 293 (2005): 2131-40. [PMID: 15870417]
• [27] Product Information. Vumerity (diroximel fumarate). Alkermes, Inc, Cambridge, MA.
• [28] Cerner Multum, Inc. "Australian Product Information.".
• [29] Product Information. Gilenya (fingolimod). Novartis Pharmaceuticals, East Hanover, NJ.
• [30] Product Information. Ocrevus (ocrelizumab). Genentech, South San Francisco, CA.
• [31] Product Information. Synribo (omacetaxine). Teva Pharmaceuticals USA, North Wales, PA.
• [32] Product Information. Arcalyst (rilonacept). Regeneron Pharmaceuticals Inc, Tarrytown, NY.
• [33] Product Information. Cimzia (certolizumab). UCB Pharma Inc, Smyrna, GA.
• [34] CDC. Centers for Disease Control and Prevention/ "Recommendations of the advisory committtee on immunization practices (ACIP): use of vaccines and immune globulins in persons with altered immunocompetence." MMWR Morb Mortal Wkly Rep 42(RR-04) (1993): 1-18. [PMID: 20300058]