Identification

Name
Pentostatin
Accession Number
DB00552  (APRD00202)
Type
Small Molecule
Groups
Approved, 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
  • Pentostatin
  • Pentostatina
  • Pentostatine
  • Pentostatinum
External IDs
CI 825 / CI-825 / NSC 218321 / NSC-218321 / PD 81565 / PD-81565 / PD-ADI / YK-176
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
International/Other Brands
Nipent
Categories
UNII
395575MZO7
CAS number
53910-25-1
Weight
Average: 268.2691
Monoisotopic: 268.11715502
Chemical Formula
C11H16N4O4
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

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).

TargetActionsOrganism
AAdenosine deaminase
inhibitor
Human
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
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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Pentostatin.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Pentostatin.Experimental
BCG vaccineThe therapeutic efficacy of BCG vaccine 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
Clostridium tetani toxoid antigen (formaldehyde inactivated)The therapeutic efficacy of Clostridium tetani toxoid antigen (formaldehyde inactivated) can be decreased when used in combination with Pentostatin.Approved
ClozapineThe risk or severity of adverse effects can be increased when Pentostatin is combined with Clozapine.Approved
Corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated)The therapeutic efficacy of Corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated) can be decreased when used in combination with Pentostatin.Approved
CyclophosphamidePentostatin may increase the cardiotoxic activities of Cyclophosphamide.Approved, Investigational
CymarinCymarin may decrease the cardiotoxic activities of Pentostatin.Experimental
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, Investigational
DigoxinDigoxin may decrease the cardiotoxic activities of Pentostatin.Approved
Digoxin Immune Fab (Ovine)Digoxin Immune Fab (Ovine) 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 therapeutic efficacy of G17DT can be decreased when used in combination with Pentostatin.Investigational
GI-5005The therapeutic efficacy of GI-5005 can be decreased when used in combination with Pentostatin.Investigational
GitoformateGitoformate may decrease the cardiotoxic activities of Pentostatin.Experimental
Hepatitis A VaccineThe therapeutic efficacy of Hepatitis A Vaccine can be decreased when used in combination with Pentostatin.Approved
Hepatitis B Vaccine (Recombinant)The therapeutic efficacy of Hepatitis B Vaccine (Recombinant) can be decreased when used in combination with Pentostatin.Approved, Withdrawn
INGN 201The therapeutic efficacy of INGN 201 can be decreased when used in combination with Pentostatin.Investigational
INGN 225The therapeutic efficacy of INGN 225 can be decreased when used in combination with Pentostatin.Investigational
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Pentostatin.Experimental
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.Investigational, Withdrawn
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Pentostatin.Experimental
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
OleandrinOleandrin may decrease the cardiotoxic activities of Pentostatin.Experimental, Investigational
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
PeruvosidePeruvoside may decrease the cardiotoxic activities of Pentostatin.Experimental
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Pentostatin.Approved, Investigational
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Pentostatin.Experimental
Rabies virus inactivated antigen, AThe risk or severity of adverse effects can be increased when Pentostatin is combined with Rabies virus inactivated antigen, A.Approved
Rabies virus inactivated antigen, AThe therapeutic efficacy of Rabies virus inactivated antigen, A can be decreased when used in combination with Pentostatin.Approved
RindopepimutThe therapeutic efficacy of Rindopepimut can be decreased when used in combination with Pentostatin.Investigational
RoflumilastRoflumilast may increase the immunosuppressive activities of Pentostatin.Approved
Rotavirus VaccineThe therapeutic efficacy of Rotavirus Vaccine can be decreased when used in combination with Pentostatin.Approved
Rubella virus vaccineThe therapeutic efficacy of Rubella virus vaccine can be decreased when used in combination with Pentostatin.Approved
Salmonella typhi ty21a live antigenThe therapeutic efficacy of Salmonella typhi ty21a live antigen can be decreased when used in combination with Pentostatin.Approved
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Pentostatin.Approved
SRP 299The therapeutic efficacy of SRP 299 can be decreased when used in combination with Pentostatin.Investigational
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Pentostatin.Approved, Investigational
TecemotideThe therapeutic efficacy of Tecemotide can be decreased when used in combination with Pentostatin.Investigational
TG4010The therapeutic efficacy of TG4010 can be decreased when used in combination with Pentostatin.Investigational
TofacitinibPentostatin may increase the immunosuppressive activities of Tofacitinib.Approved, Investigational
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Pentostatin.Approved, Investigational
Yellow fever vaccineThe therapeutic efficacy of Yellow fever vaccine can be decreased when used in combination with Pentostatin.Approved
Zoster vaccineThe therapeutic efficacy of Zoster vaccine can be decreased when used in combination with Pentostatin.Approved
Food Interactions
Not 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 References
Not Available
External Links
Human Metabolome Database
HMDB14692
KEGG Drug
D00155
KEGG Compound
C02267
PubChem Compound
439693
PubChem Substance
46507116
ChemSpider
388759
BindingDB
22925
ChEMBL
CHEMBL1580
Therapeutic Targets Database
DAP000566
PharmGKB
PA450863
HET
DCF
Drugs.com
Drugs.com Drug Page
Wikipedia
Pentostatin
ATC Codes
L01XX08 — Pentostatin
PDB Entries
1a4l / 2pgr
MSDS
Download (56.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentB-cell Non-Hodgkin's Lymphomas / Chronic Lymphocytic Leukaemia (CLL)1
1CompletedTreatmentLeukemias1
1Not Yet RecruitingTreatmentHaemoglobinopathies congenital / Sickle Cell Disorders / Thalassaemic disorders1
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) / Chronic Lymphocytic Leukaemia (CLL) / Chronic Myelogenous Leukemia, BCR-ABL1 Positive / Graft Versus Host Disease (GVHD) / Leukemia Acute Myeloid Leukemia (AML) / Lymphoma, Hodgkins / Myelodysplastic/Myeloproliferative Neoplasms / Non-Hodgkin's Lymphoma (NHL) / Plasma Cell Myeloma / Waldenstrom's Macroglobulinemia (WM)1
2Active Not RecruitingTreatmentLeukemias / Malignant Lymphomas1
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
2CompletedTreatmentEngraftment Syndrome / Graft Versus Host Disease (GVHD) / Renal Cell Adenocarcinoma1
2CompletedTreatmentGraft Versus Host Disease (GVHD)2
2CompletedTreatmentGraft Versus Host Disease (GVHD) / Immune System Disorders1
2CompletedTreatmentLeukemias / Malignant Lymphomas6
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.
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
Polarizability26.44 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
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Imidazo-meta-diazepine / Imidazodiazepine / Meta-diazepine / N-substituted imidazole / Azole / Imidazole / Heteroaromatic compound / Tetrahydrofuran / Secondary alcohol / Amidine
show 15 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Details
1. Adenosine deaminase
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, 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. [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 November 07, 2017 01:39