QuickView for Pemetrexed (compound)

Summary
General Info

PubChem

PubChem Compound 125891

Name:	pemetrexed
PubChem Compound ID:	125891
Molecular formula:	C₂₀H₁₉N₅Na₂O₆
Molecular weight:	471.375 g/mol
Synonyms:	Rolazar; Alimta; LY 231514; 150399-23-8; Tifolar; Pemetrexed disodium; LY 231514 disodium; L-Glutamic acid, N-(4-(2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo(2,3-d)pyrimidin-5-yl)ethyl)benzoyl)-, disodium salt

DrugBank

Identification

Name:	pemetrexed
Name (isomeric):	DB00642
Drug Type:	small molecule
Synonyms:	Pemetrexed Disodium; LY231514
Brand:	Alimta
Category:	Antimetabolites, Antimetabolites, Antineoplastic, Antineoplastic Agents, Enzyme Inhibitors, Folic Acid Antagonists
CAS number:	150399-23-8

Pharmacology

Indication:	Used in combination with cisplatin for the treatment of malignant pleural mesothelioma in adults whose disease is unresectable or who otherwise are not candidates for potentially curative surgery. Also used as a monotherapy for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy
Pharmacology:	Preclinical studies have shown that pemetrexed inhibits the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052). Studies with the MSTO-211H mesothelioma cell line showed synergistic effects when pemetrexed was combined concurrently with cisplatin.
Mechanism of Action:	Pemetrexed is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its antineoplastic activity by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltra... show more » Pemetrexed is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its antineoplastic activity by disrupting folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), all folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumor cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells. show less «
Protein binding:	81%
Biotransformation:	Metabolized by Cytochrome P450 Enzymes
Route of elimination:	Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration.
Half Life:	3.5 hours
Clearance:	91.8 mL/min [Cancer patients with normal renal function receiving 0.2 to 838 mg/m2 infusion over a 10-minute period]
Affected organisms:	Humans and other mammals

Interactions

Drug interaction:

Sulindac	The NSAID, sulindac, may increase the serum concentration of pemetrexed by decreasing its elimination. This interaction more prevalent in patients with mild to moderate renal insufficiency. Consider alternate therapy or monitor for pemetrexed toxicity during concomitant therapy.
Ketoprofen	The NSAID, ketoprofen, may increase increase the serum concentration of pemetrexed by decreasing its renal clearance. Patients with mild to moderate renal insufficiency (CrCl 45-79 ml/min) should avoid use of ketoprofen within 2 days of a pemetrexed dose. Patients with better renal function do not appear to be at risk. Monitor for toxicity in all patients during concomitant therapy.
Tolmetin	Tolmetin may decrease the renal excretion of Pemetrexed in patients with decreased creatinine clearance. Tolmetin may be withheld in these patients from 2 days before to 2 days after Pemetrexed administration.
Tiaprofenic acid	Tiaprofenic acid may decrease Pemetrexed excretion. Tiaprofenic acid should not be used around the time when Pemetrexed is administered.

Targets

Thymidylate synthase

Bifunctional purine biosynthesis protein PURH [Includes: Phosphoribosylaminoimidazolecarboxamide formyltransferase

Dihydrofolate reductase

UniProt ID:

P00374

Gene:

DHFR

Actions:

inhibitor

References:

Hanauske AR, Chen V, Paoletti P, Niyikiza C: Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors. Oncologist. 2001;6(4):363-73.
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Norman P: Pemetrexed disodium (Eli Lilly). Curr Opin Investig Drugs. 2001 Nov;2(11):1611-22.
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Mauritz R, Peters GJ, Priest DG, Assaraf YG, Drori S, Kathmann I, Noordhuis P, Bunni MA, Rosowsky A, Schornagel JH, Pinedo HM, Jansen G: Multiple mechanisms of resistance to methotrexate and novel antifolates in human CCRF-CEM leukemia cells and their implications for folate homeostasis. Biochem Pharmacol. 2002 Jan 15;63(2):105-15.
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Schultz RM, Dempsey JA: Sequence dependence of Alimta (LY231514, MTA) combined with doxorubicin in ZR-75-1 human breast carcinoma cells. Anticancer Res. 2001 Sep-Oct;21(5):3209-14.
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Adjei AA: Pemetrexed in the treatment of selected solid tumors. Semin Oncol. 2002 Apr;29(2 Suppl 5):50-3.
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Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5.
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Adjei AA: Gemcitabine and Pemetrexed disodium in treating breast cancer. Oncology (Williston Park). 2001 Feb;15(2 Suppl 3):34-7.
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Pivot X, Raymond E, Laguerre B, Degardin M, Cals L, Armand JP, Lefebvre JL, Gedouin D, Ripoche V, Kayitalire L, Niyikiza C, Johnson R, Latz J, Schneider M: Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck. Br J Cancer. 2001 Sep 1;85(5):649-55.
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Adjei AA: Gemcitabine and pemetrexed disodium combinations in vitro and in vivo. Lung Cancer. 2001 Dec;34 Suppl 4:S103-5.
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Molina JR, Adjei AA: The role of Pemetrexed (Alimta , LY231514) in lung cancer therapy. Clin Lung Cancer. 2003 Jul;5(1):21-7.
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Giovannetti E, Mey V, Nannizzi S, Pasqualetti G, Marini L, Del Tacca M, Danesi R: Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells. Mol Pharmacol. 2005 Jul;68(1):110-8. Epub 2005 Mar 28.
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Kindler HL: Pemetrexed in pancreatic cancer. Semin Oncol. 2002 Dec;29(6 Suppl 18):49-53.
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Trifunctional purine biosynthetic protein adenosine-3 [Includes: Phosphoribosylamine--glycine ligase

Enzymes

Deoxycytidine kinase

Equilibrative nucleoside transporter 1