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
Co-vidarabine
Nipent
Pentostatin
Pentostatina
Pentostatine
Pentostatinum
External IDs CI 825 / CI-825 / NSC 218321 / NSC-218321 / PD 81565 / PD-81565 / PD-ADI / YK-176
Product Ingredients Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
NipentInjection, powder, lyophilized, for solution2 mg/mLIntravenousHospira, Inc.1991-10-11Not applicableUs
Nipent Pws 10mg/vialPowder, for solution10 mgIntravenousParke Davis Division, Warner Lambert Canada Inc.1993-12-311997-08-25Canada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Categories
UNII395575MZO7
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[[email protected]]1O[[email protected]](C[C@@H]1O)N1C=NC2=C1N=CNC[[email protected]]2O
Pharmacology
Indication

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

Structured Indications
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).

TargetKindPharmacological actionActionsOrganismUniProt ID
Adenosine deaminaseProteinyes
inhibitor
HumanP00813 details
Related Articles
Absorption

Not absorbed orally, crosses blood brain barrier.

Volume of distributionNot 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
Toxicity

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

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
PathwaysNot Available
Pharmacogenomic Effects/ADRs Not Available
Interactions
Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Pentostatin.Approved
BCG vaccineThe therapeutic efficacy of Bcg can be decreased when used in combination with Pentostatin.Investigational
BevacizumabBevacizumab may increase the cardiotoxic activities of Pentostatin.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Pentostatin.Approved
ClozapineThe risk or severity of adverse effects can be increased when Pentostatin is combined with Clozapine.Approved
CyclophosphamidePentostatin may increase the cardiotoxic activities of Cyclophosphamide.Approved, Investigational
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Pentostatin.Approved
DeslanosideDeslanoside may decrease the cardiotoxic activities of Pentostatin.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Pentostatin.Approved
DigoxinDigoxin may decrease the cardiotoxic activities of Pentostatin.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Pentostatin.Approved, Investigational
FingolimodPentostatin may increase the immunosuppressive activities of Fingolimod.Approved, Investigational
FludarabineThe risk or severity of adverse effects can be increased when Fludarabine is combined with Pentostatin.Approved
G17DTThe risk or severity of adverse effects can be increased when Pentostatin is combined with G17DT.Investigational
INGN 201The risk or severity of adverse effects can be increased when Pentostatin is combined with INGN 201.Investigational
INGN 225The risk or severity of adverse effects can be increased when Pentostatin is combined with INGN 225.Investigational
LeflunomideThe risk or severity of adverse effects can be increased when Pentostatin is combined with Leflunomide.Approved, Investigational
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Pentostatin.Withdrawn
NatalizumabThe risk or severity of adverse effects can be increased when Pentostatin is combined with Natalizumab.Approved, Investigational
NelarabinePentostatin may decrease the antineoplastic activities of Nelarabine.Approved, Investigational
OleandrinAnvirzel may decrease the cardiotoxic activities of Pentostatin.Experimental
OuabainOuabain may decrease the cardiotoxic activities of Pentostatin.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Pentostatin.Approved, Vet Approved
Pegademase bovineThe therapeutic efficacy of Pentostatin can be decreased when used in combination with Pegademase bovine.Approved
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Pentostatin.Approved, Investigational
RindopepimutThe risk or severity of adverse effects can be increased when Pentostatin is combined with CDX-110.Investigational
RoflumilastRoflumilast may increase the immunosuppressive activities of Pentostatin.Approved
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Pentostatin.Approved
SRP 299The risk or severity of adverse effects can be increased when Pentostatin is combined with SRP 299.Investigational
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Pentostatin.Approved, Investigational
TofacitinibPentostatin may increase the immunosuppressive activities of Tofacitinib.Approved, Investigational
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Pentostatin.Approved, Investigational
Food InteractionsNot 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 ReferencesNot Available
External Links
ATC CodesL01XX08 — Pentostatin
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (56.7 KB)
Clinical Trials
Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentB-cell Non-Hodgkin's Lymphomas / Chronic Lymphocytic Leukaemia (CLL)1
1CompletedTreatmentLeukemias1
1RecruitingTreatmentLeukemia, B-Cell / Lymphoma, B-Cell / Lymphoma, Hodgkins / Non-Hodgkin's Lymphoma (NHL)1
1, 2Active Not RecruitingTreatmentAdenocarcinoma of the Lung / Mesothelioma / Neoplasms, Pancreatic1
1, 2CompletedTreatmentLeukemias / Malignant Lymphomas2
1, 2CompletedTreatmentRenal Cancers1
1, 2RecruitingTreatmentGraft Versus Host Disease (GVHD) / Sickle Cell Disorders / Thalassaemic disorders / Transplantation, Stem Cell1
1, 2RecruitingTreatmentSickle Cell Disorders1
1, 2TerminatedTreatmentAcute Graft Versus Host Disease1
1, 2WithdrawnTreatmentChronic Myeloproliferative Disorders / Leukemias / Malignant Lymphomas / Myelodysplastic Syndromes / Nonmalignant Neoplasm1
2Active Not RecruitingSupportive CareGraft Versus Host Disease (GVHD)1
2Active Not RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Acute Myeloid Leukaemias (AML) / Chronic Lymphocytic Leukaemia (CLL) / Chronic Myelogenous Leukemia, BCR-ABL1 Positive / Graft Versus Host Disease (GVHD) / Lymphoma, Hodgkins / Myelodysplastic/Myeloproliferative Neoplasms / Non-Hodgkin's Lymphoma (NHL) / Plasma Cell Myeloma / Waldenstrom's Macroglobulinemia (WM)1
2Active Not RecruitingTreatmentEngraftment Syndrome / Graft Versus Host Disease (GVHD) / Renal Cell Adenocarcinoma1
2Active Not RecruitingTreatmentLeukemias / Malignant Lymphomas2
2CompletedTreatmentAcute Lymphocytic Leukemia (ALL) / Acute Myelogenous Leukaemia (AML) / Chronic Lymphocytic Leukaemia (CLL) / Chronic Myelogenous Leukemia (CML) / Hodgkins Disease (HD) / Multiple Myeloma (MM) / Myelodysplastic Syndromes / Non-Hodgkin's Lymphoma (NHL) / Peripheral T-Cell Lymphoma (PTCL)1
2CompletedTreatmentB-Chronic Lymphocytic Leukemia1
2CompletedTreatmentChronic Lymphocytic Leukaemia (CLL)1
2CompletedTreatmentChronic Lymphocytic Leukaemia (CLL) / Cutaneous T-Cell Lymphoma (CTCL) / Peripheral T-Cell Lymphoma (PTCL)1
2CompletedTreatmentGraft Versus Host Disease (GVHD)2
2CompletedTreatmentGraft Versus Host Disease (GVHD) / Immune System Disorders1
2CompletedTreatmentLeukemias / Malignant Lymphomas5
2CompletedTreatmentLeukemias / Myelodysplastic Syndromes / Myelodysplastic/Myeloproliferative Neoplasms1
2CompletedTreatmentMalignancies, Hematologic2
2CompletedTreatmentMalignant Lymphomas1
2RecruitingTreatmentHairy Cell Leukemia (HCL)1
2TerminatedTreatmentHodgkins Disease (HD) / Leukemias / Malignant Lymphomas / Multiple Myeloma (MM) / Neoplasms, Hematologic / Renal Cell Adenocarcinoma1
2TerminatedTreatmentLeukemias / Malignant Lymphomas1
2TerminatedTreatmentMalignant Lymphomas1
2Unknown StatusTreatmentB-Cell Chronic Lymphocytic Leukemia / B-cell Non-Hodgkin's Lymphomas / Immunocytoma/Morbus Waldenström1
2Unknown StatusTreatmentB-Cell Chronic Lymphocytic Leukemia / Contiguous Stage II Small Lymphocytic Lymphoma / Hematopoietic/Lymphoid Cancer / Noncontiguous Stage II Small Lymphocytic Lymphoma / Stage 0 Chronic Lymphocytic Leukemia / Stage I Chronic Lymphocytic Leukemia / Stage I Small Lymphocytic Lymphoma / Stage II Chronic Lymphocytic Leukemia / Stage III Chronic Lymphocytic Leukemia / Stage III Small Lymphocytic Lymphoma / Stage IV Chronic Lymphocytic Leukemia / Stage IV Small Lymphocytic Lymphoma1
2Unknown StatusTreatmentLeukemias1
2WithdrawnTreatmentActive Chronic Graft Versus Host Disease1
3CompletedTreatmentAcute Lymphoblastic Leukaemias (ALL) / Acute Myelocytic Leukemia / Chronic Myelocytic Leukemia / Hodgkins Disease (HD) / Myelodysplastic Syndrome1
3CompletedTreatmentB-Cell Chronic Lymphocytic Leukemia1
3RecruitingTreatmentGraft Versus Host Disease (GVHD)1
4Unknown StatusTreatmentChronic Lymphocytic Leukaemia (CLL)1
Pharmacoeconomics
Manufacturers
  • Hospira inc
  • Bedford laboratories
Packagers
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous2 mg/mL
Powder, for solutionIntravenous10 mg
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.
PatentsNot Available
Properties
StateSolid
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
Polarizability26.44 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
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassImidazodiazepines
Sub ClassNot Available
Direct ParentImidazodiazepines
Alternative Parents1,3-diazepines / N-substituted imidazoles / Tetrahydrofurans / Heteroaromatic compounds / Secondary alcohols / Propargyl-type 1,3-dipolar organic compounds / Oxacyclic compounds / Formamidines / Carboxamidines / Azacyclic compounds
SubstituentsImidazo-meta-diazepine / Imidazodiazepine / Meta-diazepine / N-substituted imidazole / Azole / Imidazole / Heteroaromatic compound / Tetrahydrofuran / Secondary alcohol / Amidine
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available

Targets

Kind
Protein
Organism
Human
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, and so contributes indirectly to cellular signaling events. Acts as a positive regulator of T-cell coactivation, by binding DPP4. Its interaction with DPP4 regulates lymphocyte-epithelial cell adhesion.
Gene Name:
ADA
Uniprot ID:
P00813
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. [PubMed:11752352 ]
  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:2433905 ]
  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:17309302 ]
  4. Cabanillas F: Purine nucleoside analogs in indolent non-Hodgkin's lymphoma. Oncology (Williston Park). 2000 Jun;14(6 Suppl 2):13-5. [PubMed:10887639 ]
Drug created on June 13, 2005 07:24 / Updated on July 18, 2017 16:50