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Identification
NamePentostatin
Accession NumberDB00552  (APRD00202)
TypeSmall Molecule
GroupsApproved, Investigational
Description

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. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
Co-vidarabineNot AvailableIS
NipentNot AvailableNot Available
PentostatinGermanINN
PentostatinaSpanishINN
PentostatineFrenchINN
PentostatinumLatinINN
SaltsNot Available
Brand names
NameCompany
NipentSuperGen
Brand mixturesNot Available
Categories
CAS number53910-25-1
WeightAverage: 268.2691
Monoisotopic: 268.11715502
Chemical FormulaC11H16N4O4
InChI KeyFPVKHBSQESCIEP-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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganooxygen Compounds
ClassCarbohydrates and Carbohydrate Conjugates
SubclassGlycosyl Compounds
Direct parentGlycosylamines
Alternative parentsPentoses; Imidazodiazepines; 1,3-Diazepines; N-substituted Imidazoles; Oxolanes; Tetrahydrofurans; Secondary Alcohols; Primary Alcohols; Ethers; Carboxamidines; Polyamines
Substituentsimidazo-meta-diazepine; imidazodiazepine; pentose monosaccharide; meta-diazepine; n-substituted imidazole; monosaccharide; tetrahydrofuran; oxolane; azole; imidazole; secondary alcohol; primary alcohol; ether; polyamine; amidine; carboxylic acid amidine; alcohol; organonitrogen compound; amine
Classification descriptionThis compound belongs to the glycosylamines. These are compounds consisting of an amine with a β-N-glycosidic bond to a carbohydrate, thus forming a cyclic hemiaminal ether bond (α-aminoether).
Pharmacology
IndicationFor the treatment of hairy cell leukaemia refractory to alpha interferon.
PharmacodynamicsPentostatin 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 actionPentostatin 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).
AbsorptionNot absorbed orally, crosses blood brain barrier.
Volume of distributionNot Available
Protein binding4%
Metabolism

Primarily hepatic, but only small amounts are metabolized.

Route of eliminationIn 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 life5.7 hours (with a range between 2.6 and 16 hrs)
Clearance
  • 68 mL/min/m2
ToxicityLD50=128 mg/kg (mouse), side effects include lethargy, rash, fatigue, nausea and myelosuppression.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.8204
Blood Brain Barrier + 0.911
Caco-2 permeable - 0.7031
P-glycoprotein substrate Substrate 0.6194
P-glycoprotein inhibitor I Non-inhibitor 0.8993
P-glycoprotein inhibitor II Non-inhibitor 0.89
Renal organic cation transporter Non-inhibitor 0.8513
CYP450 2C9 substrate Non-substrate 0.7946
CYP450 2D6 substrate Non-substrate 0.7974
CYP450 3A4 substrate Substrate 0.5207
CYP450 1A2 substrate Non-inhibitor 0.8771
CYP450 2C9 substrate Non-inhibitor 0.9117
CYP450 2D6 substrate Non-inhibitor 0.9211
CYP450 2C19 substrate Non-inhibitor 0.8969
CYP450 3A4 substrate Non-inhibitor 0.9421
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9626
Ames test Non AMES toxic 0.7627
Carcinogenicity Non-carcinogens 0.8039
Biodegradation Not ready biodegradable 0.9961
Rat acute toxicity 2.2716 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.987
hERG inhibition (predictor II) Non-inhibitor 0.6424
Pharmacoeconomics
Manufacturers
  • Hospira inc
  • Bedford laboratories
Packagers
Dosage formsNot Available
Prices
Unit descriptionCostUnit
Pentostatin 10 mg vial2280.0USDvial
Nipent 10 mg vial1891.31USDvial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point220 °CPhysProp
water solubility30 mg/mLNot Available
logP-1.1Not Available
pKa5.2MERCK INDEX (1996)
Predicted Properties
PropertyValueSource
Water Solubility10.7ALOGPS
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
Polarizability26.44 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

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

US20040181052
General Reference
  1. Link
External Links
ResourceLink
KEGG DrugD00155
KEGG CompoundC02267
PubChem Compound439693
PubChem Substance46507116
ChemSpider37371
BindingDB50003603
Therapeutic Targets DatabaseDAP000566
PharmGKBPA450863
Drug Product Database2011247
Drugs.comhttp://www.drugs.com/cdi/pentostatin.html
WikipediaPentostatin
ATC CodesL01XX08
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(56.7 KB)
Interactions
Drug Interactions
Drug
CyclophosphamideIncreased toxicity of cyclophosphamide
FludarabineUnacceptable pulmonary toxicity
Pegademase bovineAvoid combination due to decreased effect of both drugs
TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food InteractionsNot Available

Targets

1. Adenosine deaminase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Adenosine deaminase P00813 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  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. Pubmed
  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. Pubmed
  4. Cabanillas F: Purine nucleoside analogs in indolent non-Hodgkin’s lymphoma. Oncology (Williston Park). 2000 Jun;14(6 Suppl 2):13-5. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on February 18, 2014 20:51