Pentostatin

Identification

Summary

Pentostatin is an adenosine deaminase inhibitor used to treat hairy cell leukemia.

Brand Names
Nipent
Generic Name
Pentostatin
DrugBank Accession Number
DB00552
Background

A potent inhibitor of adenosine deaminase. The drug is effective in the treatment of many lymphoproliferative malignancies, particularly hairy-cell leukemia. It is also synergistic with some other antineoplastic agents and has immunosuppressive activity.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 268.2691
Monoisotopic: 268.11715502
Chemical Formula
C11H16N4O4
Synonyms
  • Co-vidarabine
  • Pentostatin
  • Pentostatina
  • Pentostatine
  • Pentostatinum
External IDs
  • CI 825
  • CI-825
  • NSC 218321
  • NSC-218321
  • PD 81565
  • PD-81565
  • PD-ADI
  • YK-176

Pharmacology

Indication

For the treatment of hairy cell leukaemia refractory to alpha interferon.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofAcute graft versus host disease••• •••••
Treatment ofChronic lymphocytic leukemia••• •••••
Treatment ofHairy cell leukaemia••••••••••••
Treatment ofMycosis fungoides••• •••••
Treatment ofSezary syndrome••• •••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Pentostatin is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute nonlymphocytic leukemia and hairy cell leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. It is a 6-thiopurine analogue of the naturally occurring purine bases hypoxanthine and guanine. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Cytotoxicity is cell cycle phase-specific (S-phase).

Mechanism of action

Pentostatin is a potent transition state inhibitor of adenosine deaminase (ADA), the greatest activity of which is found in cells of the lymphoid system. T-cells have higher ADA activity than B-cells, and T-cell malignancies have higher activity than B-cell malignancies. The cytotoxicity that results from prevention of catabolism of adenosine or deoxyadenosine is thought to be due to elevated intracellular levels of dATP, which can block DNA synthesis through inhibition of ribonucleotide reductase. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Cytotoxicity is cell cycle phase-specific (S-phase).

TargetActionsOrganism
AAdenosine deaminase
inhibitor
Humans
Absorption

Not absorbed orally, crosses blood brain barrier.

Volume of distribution

Not Available

Protein binding

4%

Metabolism

Primarily hepatic, but only small amounts are metabolized.

Route of elimination

In man, following a single dose of 4 mg/m2 of pentostatin infused over 5 minutes, approximately 90% of the dose was excreted in the urine as unchanged pentostatin and/or metabolites as measured by adenosine deaminase inhibitory activity.

Half-life

5.7 hours (with a range between 2.6 and 16 hrs)

Clearance
  • 68 mL/min/m2
Adverse Effects
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Toxicity

LD50=128 mg/kg (mouse), side effects include lethargy, rash, fatigue, nausea and myelosuppression.

Pathways
Not Available
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Not Available

Interactions

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This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Pentostatin which could result in a higher serum level.
AbataceptThe risk or severity of adverse effects can be increased when Pentostatin is combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Pentostatin.
AceclofenacAceclofenac may decrease the excretion rate of Pentostatin which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Pentostatin which could result in a higher serum level.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
NipentInjection, powder, lyophilized, for solution2 mg/1mLIntravenousHospira, Inc.2007-08-15Not applicableUS flag
Nipent Pws 10mg/vialPowder, for solution10 mg / vialIntravenousParke Davis Division, Warner Lambert Canada Inc.1993-12-311997-08-25Canada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
PentostatinInjection, powder, lyophilized, for solution2 mg/1mLIntravenousMylan Institutional LLC2014-09-19Not applicableUS flag
PentostatinInjection, powder, lyophilized, for solution10 mg/5mLIntravenousBedford Pharmaceuticals2007-08-132012-08-31US flag

Categories

ATC Codes
L01XX08 — Pentostatin
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as imidazodiazepines. These are organic compounds containing an imidazole ring fused to a diazepine ring. Imidazole is 5-membered ring consisting of three carbon atoms, and two nitrogen centers at the 1- and 3-positions. Diazepine is a 7-membered ring consisting of five carbon and two nitrogen atoms.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Imidazodiazepines
Sub Class
Not Available
Direct Parent
Imidazodiazepines
Alternative Parents
1,3-diazepines / N-substituted imidazoles / Tetrahydrofurans / Heteroaromatic compounds / Secondary alcohols / Propargyl-type 1,3-dipolar organic compounds / Oxacyclic compounds / Formamidines / Carboxamidines / Azacyclic compounds
show 3 more
Substituents
Alcohol / Amidine / Aromatic heteropolycyclic compound / Azacycle / Azole / Carboxylic acid amidine / Formamidine / Heteroaromatic compound / Hydrocarbon derivative / Imidazo-meta-diazepine
show 15 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals
  • Mycobacterium tuberculosis
  • Pseudomonas aeruginosa
  • Leptospira interrogans
  • Borrelia burgdorferi
  • Vibrio cholerae
  • Escherichia coli
  • Salmonella typhi
  • Staphylococcus aureus
  • Serratia marcescens
  • Proteus vulgaris
  • Klebsiella
  • Shigella

Chemical Identifiers

UNII
395575MZO7
CAS number
53910-25-1
InChI Key
FPVKHBSQESCIEP-JQCXWYLXSA-N
InChI
InChI=1S/C11H16N4O4/c16-3-8-6(17)1-9(19-8)15-5-14-10-7(18)2-12-4-13-11(10)15/h4-9,16-18H,1-3H2,(H,12,13)/t6-,7+,8+,9+/m0/s1
IUPAC Name
(8R)-3-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3H,6H,7H,8H-imidazo[4,5-d][1,3]diazepin-8-ol
SMILES
OC[C@H]1O[C@H](C[C@@H]1O)N1C=NC2=C1N=CNC[C@H]2O

References

Synthesis Reference

Nadji Sourena, "Process for the production of pentostatin aglycone and pentostatin." U.S. Patent US20040181052, issued September 16, 2004.

US20040181052
General References
Not Available
Human Metabolome Database
HMDB0014692
KEGG Drug
D00155
KEGG Compound
C02267
PubChem Compound
439693
PubChem Substance
46507116
ChemSpider
388759
BindingDB
223291
RxNav
8011
ChEMBL
CHEMBL1580
ZINC
ZINC000003806262
Therapeutic Targets Database
DAP000566
PharmGKB
PA450863
PDBe Ligand
DCF
Drugs.com
Drugs.com Drug Page
Wikipedia
Pentostatin
PDB Entries
1a4l / 2pgr / 6n91 / 6n9m
MSDS
Download (56.7 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Pharmacoeconomics

Manufacturers
  • Hospira inc
  • Bedford laboratories
Packagers
  • Bedford Labs
  • Ben Venue Laboratories Inc.
  • Hospira Inc.
  • JHP Pharmaceuticals LLC
  • SuperGen Inc.
Dosage Forms
FormRouteStrength
Tablet, coatedOral500 mg
Injection, powder, lyophilized, for solutionIntravenous2 mg/1mL
Powder, for solutionIntravenous10 mg
Powder, for solutionIntravenous10 mg / vial
Injection, powder, lyophilized, for solutionIntravenous10 mg/5mL
Prices
Unit descriptionCostUnit
Pentostatin 10 mg vial2280.0USD vial
Nipent 10 mg vial1891.31USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)220 °CPhysProp
water solubility30 mg/mLNot Available
logP-1.1Not Available
pKa5.2MERCK INDEX (1996)
Predicted Properties
PropertyValueSource
Water Solubility10.7 mg/mLALOGPS
logP-2ALOGPS
logP-2Chemaxon
logS-1.4ALOGPS
pKa (Strongest Acidic)13.06Chemaxon
pKa (Strongest Basic)8.33Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count7Chemaxon
Hydrogen Donor Count4Chemaxon
Polar Surface Area112.13 Å2Chemaxon
Rotatable Bond Count2Chemaxon
Refractivity64.98 m3·mol-1Chemaxon
Polarizability26.34 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.8204
Blood Brain Barrier+0.911
Caco-2 permeable-0.7031
P-glycoprotein substrateSubstrate0.6194
P-glycoprotein inhibitor INon-inhibitor0.8993
P-glycoprotein inhibitor IINon-inhibitor0.89
Renal organic cation transporterNon-inhibitor0.8513
CYP450 2C9 substrateNon-substrate0.7946
CYP450 2D6 substrateNon-substrate0.7974
CYP450 3A4 substrateSubstrate0.5207
CYP450 1A2 substrateNon-inhibitor0.8771
CYP450 2C9 inhibitorNon-inhibitor0.9117
CYP450 2D6 inhibitorNon-inhibitor0.9211
CYP450 2C19 inhibitorNon-inhibitor0.8969
CYP450 3A4 inhibitorNon-inhibitor0.9421
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9626
Ames testNon AMES toxic0.7627
CarcinogenicityNon-carcinogens0.8039
BiodegradationNot ready biodegradable0.9961
Rat acute toxicity2.2716 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.987
hERG inhibition (predictor II)Non-inhibitor0.6424
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-000f-9280000000-53989a5cd0535c5bb1c0
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0uy0-0940000000-a88656b673e87d4ddcf2
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-0190000000-afde3d1df779eba4994b
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0900000000-14738a737e65dcd87d0f
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0f79-0920000000-7f9e2d4f716b5e306d38
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-00lr-0930000000-95e87132ba6fb03553fd
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a59-0900000000-51b08dc9c03d76205489
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-168.7090928
predicted
DarkChem Lite v0.1.0
[M-H]-169.0596928
predicted
DarkChem Lite v0.1.0
[M-H]-168.8442928
predicted
DarkChem Lite v0.1.0
[M-H]-151.88477
predicted
DeepCCS 1.0 (2019)
[M+H]+169.2249928
predicted
DarkChem Lite v0.1.0
[M+H]+169.3066928
predicted
DarkChem Lite v0.1.0
[M+H]+169.2039928
predicted
DarkChem Lite v0.1.0
[M+H]+154.28032
predicted
DeepCCS 1.0 (2019)
[M+Na]+169.1211928
predicted
DarkChem Lite v0.1.0
[M+Na]+168.9916928
predicted
DarkChem Lite v0.1.0
[M+Na]+168.8924928
predicted
DarkChem Lite v0.1.0
[M+Na]+160.62367
predicted
DeepCCS 1.0 (2019)

Targets

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Details
1. Adenosine deaminase
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Catalyzes the hydrolytic deamination of adenosine and 2-deoxyadenosine. Plays an important role in purine metabolism and in adenosine homeostasis. Modulates signaling by extracellular adenosine, an...
Gene Name
ADA
Uniprot ID
P00813
Uniprot Name
Adenosine deaminase
Molecular Weight
40764.13 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  2. Jackson RC, Leopold WR, Ross DA: The biochemical pharmacology of (2'-R)-chloropentostatin, a novel inhibitor of adenosine deaminase. Adv Enzyme Regul. 1986;25:125-39. [Article]
  3. Newman DJ, Cragg GM: Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. Epub 2007 Feb 20. [Article]
  4. Cabanillas F: Purine nucleoside analogs in indolent non-Hodgkin's lymphoma. Oncology (Williston Park). 2000 Jun;14(6 Suppl 2):13-5. [Article]

Drug created at June 13, 2005 13:24 / Updated at December 02, 2023 06:52