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IdentificationPharmacologyInteractionsReferencesTrialsEconomicsPropertiesSpectraTaxonomyIdentification
- Name
- Pralatrexate
- Accession Number
- DB06813 (DB05527)
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Description
Pralatrexate is an antimetabolite for the treatment of relapsed or refractory peripheral T-cell lymphoma. It is more efficiently retained in cancer cells than methotrexate. FDA approved on September 24, 2009.
- Structure
Structure for Pralatrexate (DB06813)
- Synonyms
- (2S)-2-((4-((1RS)-1-((2,4-Diaminopteridin-6-yl)methyl)but-3-ynyl)benzoyl)amino)pentanedioic acid
- (2S)-2-({4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]benzoyl}amino)pentanedioic acid
- 10-Propargyl-10-deazaaminopterin
- N-(4-(1-((2,4-Diamino-6-pteridinyl)methyl)-3-butynyl)benzoyl)-L-glutamic acid
- PDX
- Pralatrexate
- Pralatrexato
- Pralatrexatum
- Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Folotyn Injection 20 mg/1mL Intravenous Allos Therapeutics 2009-09-24 Not applicable US 
- International/Other Brands
- Folotyn
- Categories
- UNII
- A8Q8I19Q20
- CAS number
- 146464-95-1
- Weight
- Average: 477.4726
Monoisotopic: 477.176066881 - Chemical Formula
- C23H23N7O5
- InChI Key
- OGSBUKJUDHAQEA-WMCAAGNKSA-N
- InChI
- InChI=1S/C23H23N7O5/c1-2-3-14(10-15-11-26-20-18(27-15)19(24)29-23(25)30-20)12-4-6-13(7-5-12)21(33)28-16(22(34)35)8-9-17(31)32/h1,4-7,11,14,16H,3,8-10H2,(H,28,33)(H,31,32)(H,34,35)(H4,24,25,26,29,30)/t14?,16-/m0/s1
- IUPAC Name
- (2S)-2-({4-[1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl]phenyl}formamido)pentanedioic acid
- SMILES
- NC1=NC2=NC=C(CC(CC#C)C3=CC=C(C=C3)C(=O)N[C@@H](CCC(O)=O)C(O)=O)N=C2C(N)=N1
Pharmacology
- Indication
Treatment of relapsed or refractory peripheral T-cell lymphoma.
- Associated Conditions
- Pharmacodynamics
Pralatrexate is a 10-deazaaminopterin analogue of methotrexate. Compared to methotrexate, pralatrexate binds to RTC-1 with 10-times the affinity and is a more potent substrate for FPGS. As a result, pralatrexate is better internalized and retained in cancer cells and is more cytotoxic. Km, pralatrexate = 0.3 μmol/L; Km, methotrexate = 4.8 μmol/L; Vmax/Km (rate of intracellular transport), pralatrexate = 12.6 Vmax/Km (rate of intracellular transport), methotrexate = 0.9
- Mechanism of action
The selectivity of pralatrexate for cancer cells is based upon the observation that cancer cells generally have an overexpression of reduced folate carrier protein-1 (RTC-1) compared to normal somatic cells. This carrier protein allows the entrance of pralatrexate into the cell. Upon entering the cell, folypolyglutamate synthase FPGS catalyzes the polyglutamination of pralatrexate so that it is retained inside the cell.
Once inside, pralatrexate competitively inhibits dihydrofolate reductase (DHFR) and thymidylate synthase. Subsequent depletion of thymidine monophosphate (TMP) occurs so that the cancer cell is unable to synthesize DNA and RNA. As a result, the cancer cell cannot proliferate and is forced to undergo apoptosis. Pralatrexate is more effective against cells that are actively dividing.Target Actions Organism ADihydrofolate reductase inhibitorHumans AThymidylate synthase inhibitorHumans - Absorption
Pralatrexate demonstrates linear pharmacokinetics with a multiphasic decline with both diasteromers over dose range of 30-325 mg/m^2. Bioavailability, nonformulated preparation = 13 - 20%
- Volume of distribution
Vss, R-pralatrexate = 37 L Vss, S-pralatrexate = 105 L
- Protein binding
67 - 86% bound to plasma protein, albumin is the major binder. Does not significantly displace substrates from proteins.
- Metabolism
No involvement of CYP450 enzyme system or glucuronidases.
- Route of elimination
35% of drug is excreted unchanged in the urine (no difference between R- and S- pralatrexate). May be some net renal tubular excretion.
- Half life
12-18 hours
- Clearance
R- pralatrexate = 191 mL/min S- pralatrexate = 417 mL/min Mean clearance of both enantiomers is 220 mL/min.
- Toxicity
Mucositis is the dose-limiting toxicity. Folic acid and vitamin B12 supplements do not prevent mucositis from happening.
- Affected organisms
- Humans and other mammals
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
Drug Interaction (6R)-Folinic acid The therapeutic efficacy of Pralatrexate can be decreased when used in combination with (6R)-Folinic acid. (6S)-5,6,7,8-tetrahydrofolate The therapeutic efficacy of Pralatrexate can be decreased when used in combination with (6S)-5,6,7,8-tetrahydrofolate. 2-Methoxyethanol The risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Pralatrexate. 9-(N-methyl-L-isoleucine)-cyclosporin A The risk or severity of adverse effects can be increased when Pralatrexate is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A. Abacavir Abacavir may decrease the excretion rate of Pralatrexate which could result in a higher serum level. Abatacept The risk or severity of adverse effects can be increased when Abatacept is combined with Pralatrexate. Abetimus The risk or severity of adverse effects can be increased when Abetimus is combined with Pralatrexate. Acarbose Acarbose may decrease the excretion rate of Pralatrexate which could result in a higher serum level. Aceclofenac Aceclofenac may decrease the excretion rate of Pralatrexate which could result in a higher serum level. Acemetacin Acemetacin may decrease the excretion rate of Pralatrexate which could result in a higher serum level. - Food Interactions
- Not Available
References
- General References
- Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799]
- Gonen N, Assaraf YG: Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012 Aug;15(4):183-210. doi: 10.1016/j.drup.2012.07.002. Epub 2012 Aug 23. [PubMed:22921318]
- Rodd AL, Ververis K, Karagiannis TC: Safety and efficacy of pralatrexate in the management of relapsed or refractory peripheral T-cell lymphoma. Clin Med Insights Oncol. 2012;6:305-14. doi: 10.4137/CMO.S8536. Epub 2012 Aug 21. [PubMed:23032692]
- External Links
- KEGG Drug
- D05589
- PubChem Compound
- 148121
- PubChem Substance
- 175427094
- ChemSpider
- 130578
- ChEBI
- 71223
- ChEMBL
- CHEMBL1201746
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Pralatrexate
- ATC Codes
- L01BA05 — Pralatrexate
- FDA label
- Download (266 KB)
- MSDS
- Download (479 KB)
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Injection Intravenous 20 mg/1mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) US6028071 No 2000-02-22 2022-07-16 US US7622470 No 2009-11-24 2025-05-31 US US8299078 No 2012-10-30 2025-05-31 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0178 mg/mL ALOGPS logP 0.1 ALOGPS logP 0.33 ChemAxon logS -4.4 ALOGPS pKa (Strongest Acidic) 3.44 ChemAxon pKa (Strongest Basic) 2.86 ChemAxon Physiological Charge -2 ChemAxon Hydrogen Acceptor Count 11 ChemAxon Hydrogen Donor Count 5 ChemAxon Polar Surface Area 207.3 Å2 ChemAxon Rotatable Bond Count 10 ChemAxon Refractivity 126.82 m3·mol-1 ChemAxon Polarizability 47.31 Å3 ChemAxon Number of Rings 3 ChemAxon Bioavailability 0 ChemAxon Rule of Five No ChemAxon Ghose Filter Yes ChemAxon Veber's Rule No ChemAxon MDDR-like Rule Yes ChemAxon - Predicted ADMET features
Property Value Probability Human Intestinal Absorption - 0.6139 Blood Brain Barrier + 0.5561 Caco-2 permeable - 0.7518 P-glycoprotein substrate Substrate 0.5845 P-glycoprotein inhibitor I Non-inhibitor 0.9224 P-glycoprotein inhibitor II Non-inhibitor 0.9921 Renal organic cation transporter Non-inhibitor 0.938 CYP450 2C9 substrate Non-substrate 0.8589 CYP450 2D6 substrate Non-substrate 0.8269 CYP450 3A4 substrate Non-substrate 0.6396 CYP450 1A2 substrate Non-inhibitor 0.8654 CYP450 2C9 inhibitor Non-inhibitor 0.8965 CYP450 2D6 inhibitor Non-inhibitor 0.9073 CYP450 2C19 inhibitor Non-inhibitor 0.9178 CYP450 3A4 inhibitor Non-inhibitor 0.6523 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.934 Ames test Non AMES toxic 0.8727 Carcinogenicity Non-carcinogens 0.9543 Biodegradation Not ready biodegradable 0.9493 Rat acute toxicity 2.6263 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9803 hERG inhibition (predictor II) Non-inhibitor 0.8735
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available MS/MS Spectrum - , positive LC-MS/MS splash10-004i-1513900000-5596beb52832aa3566cc
Taxonomy
- Description
- This compound belongs to the class of organic compounds known as glutamic acid and derivatives. These are compounds containing glutamic acid or a derivative thereof resulting from reaction of glutamic acid at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Glutamic acid and derivatives
- Alternative Parents
- N-acyl-alpha amino acids / Hippuric acids / Pteridines and derivatives / Aromatic monoterpenoids / Bicyclic monoterpenoids / Benzoyl derivatives / Aminopyrimidines and derivatives / Pyrazines / Imidolactams / Dicarboxylic acids and derivatives show 11 more
- Substituents
- Glutamic acid or derivatives / Hippuric acid / N-acyl-alpha-amino acid / N-acyl-alpha amino acid or derivatives / Hippuric acid or derivatives / P-cymene / Aromatic monoterpenoid / Monoterpenoid / Bicyclic monoterpenoid / Pteridine show 29 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- terminal acetylenic compound, N-acyl-L-glutamic acid, pteridines (CHEBI:71223)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Nadph binding
- Specific Function
- Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA pre...
- Gene Name
- DHFR
- Uniprot ID
- P00374
- Uniprot Name
- Dihydrofolate reductase
- Molecular Weight
- 21452.61 Da
References
- Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Thymidylate synthase activity
- Specific Function
- Contributes to the de novo mitochondrial thymidylate biosynthesis pathway.
- Gene Name
- TYMS
- Uniprot ID
- P04818
- Uniprot Name
- Thymidylate synthase
- Molecular Weight
- 35715.65 Da
References
- Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Tetrahydrofolylpolyglutamate synthase activity
- Specific Function
- Catalyzes conversion of folates to polyglutamate derivatives allowing concentration of folate compounds in the cell and the intracellular retention of these cofactors, which are important substrate...
- Gene Name
- FPGS
- Uniprot ID
- Q05932
- Uniprot Name
- Folylpolyglutamate synthase, mitochondrial
- Molecular Weight
- 64608.53 Da
References
- Shimanovsky A, Dasanu CA: Pralatrexate : evaluation of clinical efficacy and toxicity in T-cell lymphoma. Expert Opin Pharmacother. 2013 Mar;14(4):515-23. doi: 10.1517/14656566.2013.770474. Epub 2013 Feb 14. [PubMed:23409799]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Reduced folate carrier activity
- Specific Function
- Transporter for the intake of folate. Uptake of folate in human placental choriocarcinoma cells occurs by a novel mechanism called potocytosis which functionally couples three components, namely th...
- Gene Name
- SLC19A1
- Uniprot ID
- P41440
- Uniprot Name
- Folate transporter 1
- Molecular Weight
- 64867.62 Da
References
- Gonen N, Assaraf YG: Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012 Aug;15(4):183-210. doi: 10.1016/j.drup.2012.07.002. Epub 2012 Aug 23. [PubMed:22921318]
Drug created on September 14, 2010 10:21 / Updated on January 14, 2019 10:12