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Pentostatin

PubChem CID
439693
Structure
Pentostatin_small.png
Pentostatin_3D_Structure.png
Molecular Formula
Synonyms
  • pentostatin
  • Deoxycoformycin
  • Nipent
  • 53910-25-1
  • 2'-Deoxycoformycin
Molecular Weight
268.27 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-06-24
  • Modify:
    2025-01-18
Description
Pentostatin can cause developmental toxicity according to state or federal government labeling requirements.
Pentostatin is a member of the class of coformycins that is coformycin in which the hydroxy group at position 2' is replaced with a hydrogen. It is a drug used for the treatment of hairy cell leukaemia. It has a role as an EC 3.5.4.4 (adenosine deaminase) inhibitor, an antineoplastic agent, an antimetabolite, a bacterial metabolite and an Aspergillus metabolite. It is a conjugate base of a pentostatin(1+).
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.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Pentostatin.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

(8R)-3-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7,8-dihydro-4H-imidazo[4,5-d][1,3]diazepin-8-ol
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 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
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

FPVKHBSQESCIEP-JQCXWYLXSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

C1[C@@H]([C@H](O[C@H]1N2C=NC3=C2NC=NC[C@H]3O)CO)O
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C11H16N4O4
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 Deprecated CAS

59979-24-7, 63677-95-2, 69196-00-5, 70865-77-9
63677-95-2, 69196-00-5, 70865-77-9

2.3.3 European Community (EC) Number

2.3.4 UNII

2.3.5 ChEBI ID

2.3.6 ChEMBL ID

2.3.7 DrugBank ID

2.3.8 DSSTox Substance ID

2.3.9 HMDB ID

2.3.10 KEGG ID

2.3.11 Metabolomics Workbench ID

2.3.12 NCI Thesaurus Code

2.3.13 Nikkaji Number

2.3.14 PharmGKB ID

2.3.15 Pharos Ligand ID

2.3.16 RXCUI

2.3.17 Wikidata

2.3.18 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • 2' Deoxycoformycin
  • 2'-Deoxycoformycin
  • CI 825
  • CI-825
  • CI825
  • Co-vidarabine
  • Deoxycoformycin
  • Imidazo(4,5-d)(1,3)diazepin-8-ol, 3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,4,7,8-tetrahydro-, (R)-
  • Nipent
  • NSC 218321
  • NSC-218321
  • NSC218321
  • Pentostatin

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
268.27 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
-2.1
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
4
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
6
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
268.11715500 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
268.11715500 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
112 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
19
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
356
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
4
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Color / Form

White crystals from methanol/water
Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 1131
White to off-white solid
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 632

3.2.3 Melting Point

220 °C
PhysProp
220-225 °C
Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 1131
Mp: also reported as 204-209.5 °C with darkening at > 150 °C.
Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 1131
220 °C

3.2.4 Solubility

30 mg/mL
Freely soluble in water, aqueous solubility > 100 mg/ml
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 632
1.07e+01 g/L
H2O >30 (mg/mL)
pH 9 borate buffer >50 (mg/mL)

3.2.5 LogP

-1.1
-1.1

3.2.6 Stability / Shelf Life

Commercially available pentostatin powder for injection should be stored at 2-8 °C. ... When stored at 2-8 °C, the manufacturer states that currently available pentostatin powder for injection is stable for 18 mo after the date of manufacture when stored as directed. ... Pentostatin is compatible with 5% dextrose injection, 0.9% sodium chloride injection, and lactated Ringer's. When reconstituted with 0.9% sodium chloride injection to a final concentration of 2 mg/ml, pentostatin solutions are physically and chemically stable for at least 72 hr at room temperature (22-25 °C). When diluted to a final concentration of 20 ug/ml, the drug is chemically compatible at room temperature with 0.9% sodium chloride or lactated Ringer's injection for at least 48 hr and with 5% dextrose injection for at least 24 hr. Up to an 8-10% loss in potency has been reported to occur within 48 hr in such solutions diluted in 5% dextrose, However, because such reconstituted and/or diluted pentostatin solutions contain no preservatives, the manufacturer recommends that they be used within 8 hr when stored at room temperature in ambient light, and that unused portions be discarded.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 633
Stability
Bulk: Bulk samples stored at 60 °C for 9 days showed no decomposition (TLC and UV). Bulk material should be stored at -20 °C for long term storage.

3.2.7 Optical Rotation

Specific optical rotation: + 76.4 deg at 25 °C/D (concentration by volume = 1 g 100 ml water); specific optical rotation: + 73.0 deg at 23 °C/D (concentration by volume = 1 g in 100 ml water pH 7 buffer)
Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 1131
(c = 1, H2O) [a]25D = +76.4 ± 2°

3.2.8 Dissociation Constants

pKa
5.2
MERCK INDEX (1996)
pKa = 5.2 in water
Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 1131

3.2.9 Other Experimental Properties

Pentostatin differs from the physiologic nucleosides, adenosine and deoxyadenosine, by the interposition of a methylene group between N-1 and C-6 of the purine ring, resulting in a 7-membered (imidazobenzopin) rather than a 6-membered ring, and by the deletion of an amino group from, and the addition of a hydroxyl group to, the ring; the sugar moiety, deoxyribose, is common to both pentostatin and deoxyadenosine, while adenosine contains ribose. The resultant stereochemical and tautomeric differences in the compounds provide an increased binding affinity of pentostatin for the catalytic center of adenosine deaminase compared with the affinities of these physiologic substrates for the enzyme. Pentostatin is thought to resemble closely the transition-state intermediates of the adenosine deaminase reaction involving these nucleosides (ie, the intermediaries formed during the deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively), The drug is a purine antagonist antimetabolite that acts as an adenosine deaminase inhibitor.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 632

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
3.3.1.1 Human Drugs
Human drug -> Prescription
Human drug -> Prescription; Discontinued; Active ingredient (PENTOSTATIN)

4 Spectral Information

4.1 Mass Spectrometry

4.1.1 LC-MS

MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M+2H]+
Precursor m/z
135.066
Instrument
Orbitrap
Ionization Mode
positive
Top 5 Peaks

135.066498 100

136.050461 27.53

108.055649 22.26

81.044930 12.49

118.039948 9.30

Thumbnail
Thumbnail

4.2 UV Spectra

Max absorption: (water, pH7) 282 nm (E= 8000); (pH 11) 283 nm (E= 7970); (pH 2) 273 nm (E= 7570 initially, 3143 after 6.5 hr)
Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 1131
(pH 9 borate buffer) max = 283 ± 2 nm E = 7,950 - 8,250

4.3 Chromatograms

4.3.1 HPLC

HPLC
Column: uBondapak C18 300 x 3.9 mm i.d. Mobile Phase: CH3OH/0.01 M phosphate buffer (pH 7), 13/87, v/v Flow Rate: 1.0 mL/min Detection: UV at 254 nm Sample Preparation: 0.1 mg/mL in internal standard solution Internal Standard: acetanilide (0.3 mg/mL in mobile phase) Retention Volume: 7.2 mL (NSC- 218321) 28 mL (I.S.)

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

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

7.2 LiverTox Summary

Pentostatin is a purine analogue and antineoplastic agent used in the therapy of hairy cell leukemia and T cell lymphomas. Pentostatin is associated with a low rate of serum enzyme elevations during therapy and has been linked to rare instances of severe acute liver injury with jaundice.

7.3 Drug Classes

Antineoplastic Agents

7.4 FDA Approved Drugs

7.5 FDA Orange Book

7.6 FDA National Drug Code Directory

7.7 Drug Labels

Drug and label
Active ingredient and drug

7.8 Clinical Trials

7.8.1 ClinicalTrials.gov

7.8.2 EU Clinical Trials Register

7.9 Therapeutic Uses

Antibiotics; Antineoplastic Agents; Enzyme Inhibitors; Immunosuppressive Agents
National Library of Medicine's Medical Subject Headings online file (MeSH, 2000)
Antibiotics, Antineoplastic; Enzyme Inhibitors; Immunosuppressive Agents
National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)
Antineoplastic
Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 1131
Pentostatin is used for the palliative treatment of hairy cell leukemia (leukemic reticuloendotheliosis) that responds inadequately to, or progresses during, interferon alfa therapy. Pentostatin has been designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this condition. ... Pentostatin produces clinically important tumor regression or disease stabilization (complete or partial responses) in approximately 80-100% of patients with hairy cell leukemia, including in previously untreated patients (eg, those who have not undergone splenectomy or other therapy) as well as in those in whom splenectomy and/or therapy with other agents (eg, interferons, antineoplastic agents) have failed to control the disease (eg, those with progressive disease). In clinical studies in patients with interferon alfa-refractory hairy cell leukemia, a complete response to pentostatin therapy generally was defined as clearing of peripheral blood and bone marrow of hairy cells; normalization of organomegaly and lymphadenopathy; and recovery of hemoglobin concentration to at least 12 g/dl, platelet count to at least 100,000/cu mm, and granulocyte count to at least 1500/cu mm. A partial response was defined as a decrease of greater than 50% in the number of hairy cells in peripheral blood and bone marrow and a decrease of greater than 50% in organomegaly and lymphadenopathy; hematologic parameters for a partial response were the same as those for a complete response. Overall complete and partial responses of 58 and 28%, respectively, reportedly were observed in a limited number of these patients receiving pentostatin 4 mg/sq m iv every other week for 3 mo; responding patients continued treatment for another 3-9 mos. The median time to response in these patients reportedly was 4.7 mo (range: 2.9-24.1 mo). The median duration of response to pentostatin therapy in 2 clinical studies of patients with hairy cell leukemia reportedly exceeded 7.7 and 15.2 mo, with relapse occurring in approximately 15-20% of patients showing an initial response. For patients with progressive, postsplenectomy disease, pentostatin generally has been considered an alternative to interferon alfa or secondary therapy for interferon refractory disease since experience with interferon alfa has been more extensive to date. However, superiority of either drug or of other therapies remains to be established.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 633
For more Therapeutic Uses (Complete) data for PENTOSTATIN (10 total), please visit the HSDB record page.

7.10 Drug Warnings

Pentostatin is a toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity. The drug must be used only under constant supervision by physicians experienced in therapy with cytotoxic agents. Most, but not all, adverse effects of pentostatin are reversible if detected promptly. When severe adverse effects occur during pentostatin therapy, the drug should be discontinued or dosage reduced and appropriate measures instituted. Pentostatin should be reinstituted with caution if at all, with adequate consideration of further need for the drug, and with awareness of possible recurrence of toxicity.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 636
Patients with poor performance status appear to experience greater toxicity with pentostatin and should be treated with the drug only when the anticipated benefits outweigh the potential risks.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 636
Hematologic function must be frequently and carefully monitored during and after pentostatin therapy, particularly during the first several courses of therapy in patients at increased risk of myelosuppression (eg, those with hairy cell leukemia). Initiation of pentostatin therapy in such patients can result in severe myelosuppression. If severe neutropenia continues beyond the initial cycles of pentostatin therapy, patients should be examined, including bone marrow examination, to determine the status of their disease. In addition, periodic monitoring for evidence of peripheral hairy cells should be performed in patients with this leukemia to evaluate the patient's response to therapy. Bone marrow aspirations and biopsies also may be required at 2 to 3 mo intervals.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 636
Patients receiving pentostatin should be observed closely for signs of nonhematologic (eg, neurologic) toxicity. If severe adverse reactions occur, the drug should be withheld and appropriate corrective measures taken as indicated. Therapy with pentostatin should be temporarily withheld or discontinued in patients who develop evidence of neurologic toxicity.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 636
For more Drug Warnings (Complete) data for PENTOSTATIN (11 total), please visit the HSDB record page.

8 Pharmacology and Biochemistry

8.1 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).

8.2 MeSH Pharmacological Classification

Adenosine Deaminase Inhibitors
Drugs that inhibit ADENOSINE DEAMINASE activity. (See all compounds classified as Adenosine Deaminase Inhibitors.)
Antineoplastic Agents
Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)

8.3 FDA Pharmacological Classification

1 of 2
FDA UNII
395575MZO7
Active Moiety
PENTOSTATIN
Pharmacological Classes
Mechanisms of Action [MoA] - Nucleic Acid Synthesis Inhibitors
Pharmacological Classes
Established Pharmacologic Class [EPC] - Nucleoside Metabolic Inhibitor
FDA Pharmacology Summary
Pentostatin is a Nucleoside Metabolic Inhibitor. The mechanism of action of pentostatin is as a Nucleic Acid Synthesis Inhibitor.
2 of 2
Non-Proprietary Name
PENTOSTATIN
Pharmacological Classes
Nucleoside Metabolic Inhibitor [EPC]; Nucleic Acid Synthesis Inhibitors [MoA]

8.4 ATC Code

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01X - Other antineoplastic agents

L01XX - Other antineoplastic agents

L01XX08 - Pentostatin

8.5 Absorption, Distribution and Excretion

Absorption
Not absorbed orally, crosses blood brain barrier.
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.
Clearance
68 mL/min/m2
Plasma concentrations of pentostatin following direct iv injection of 0.25 mg/kg daily for 4 or 5 days in a limited number of patients with advanced, refractory cancer ranged from approximately 3.2-9.7 ng/ml. Plasma concentrations appear to increase linearly with dose; in a study in patients with leukemia, plasma pentostatin concentrations determined 1 hour after administration of 0.25 or 1 mg/kg of the drug as a 30 min iv infusion averaged approximately 0.4 or 1.26 ug/ml, respectively.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 633
No apparent correlation has been documented between mean or absolute plasma adenosine or deoxyadenosine concentrations and therapeutic or toxic responses to pentostatin; however, limited data suggest that there may be a correlation between response to the drug and the ratio of deoxyadenosine triphosphate to adenosine triphosphate in lymphoblasts. In addition, increases in plasma deoxyadenosine reportedly parallel the accumulation of deoxyadenosine triphosphate in erythrocytes and lymphoblasts, and there appears to be a correlation between toxicity and the ratio of deoxyadenosine triphosphate to adenosine triphosphate in erythrocytes.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 633
Studies in animals indicate that pentostatin distributes rapidly to all body tissues, but the extent of drug accumulation in different tissues appears to vary among species. Following intraperitoneal injection in mice, the highest concentrations of the drug were found in the kidneys, liver, and spleen. In dogs, pentostatin tissue concentrations following iv administration were proportional to tissue adenosine deaminase activity, with the highest concentrations in the lungs, spleen, pancreas, heart, liver, and jejunum. Pentostatin reportedly enters erythrocytes via a facilitated transport system common to other nucleosides or by simple diffusion; efflux of the drug from cells has not been characterized, although the time course of pentostatin's effects (eg, adenosine deaminase inhibition) varies among different types of cells (eg, lymphocytes, erythrocytes).
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 633
Limited data in animals and humans indicate that pentostatin distributes relatively poorly into CSF, with peak CSF concentrations averaging approximately 10% of concurrent plasma concentrations. In a 6 yr old leukemia patient receiving pentostatin 0.25 mg/kg daily for 3 successive days by direct iv injection, serum and CSF (via lumbar puncture) pentostatin concentrations 4 hr after the initial dose were approximately 147 and 19 ng/ml, respectively, using an enzyme-inhibition titration assay; one hour after the third dose, corresponding serum and CSF concentrations were approximately 241 and 35 ng/ml, respectively.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 633
For more Absorption, Distribution and Excretion (Complete) data for PENTOSTATIN (7 total), please visit the HSDB record page.

8.6 Metabolism / Metabolites

Primarily hepatic, but only small amounts are metabolized.
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)

8.7 Biological Half-Life

5.7 hours (with a range between 2.6 and 16 hrs)
Following iv administration of 4 mg/sq m of pentostatin as a single dose over 5 min in healthy individuals, the distribution half-life and terminal elimination half-life reportedly averaged 11 min and 5.7 hr, respectively. In a multiple dose study in a limited number of patients receiving 36 courses of pentostatin at a dosage of 4 mg/sq m iv, distribution half-life and terminal elimination half-life reportedly averaged 9.6 min (range: 3.1-48.5 min) and 4.9 hr, respectively. In other studies in a limited number of patients with advanced cancer, the distribution half-life averaged 17-85 min and the terminal elimination half-life averaged 2.6-15 hr following single iv doses of 0.1 or 0.25 mg/kg of pentostatin.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 633
In patients with renal impairment (creatinine clearance less than 60 ml/min),the half-life of pentostatin averages approximately 18 hr.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 633

8.8 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).
... Adenosine deaminase inhibitor
Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 1131
The precise mechanism(s) of action of pentostatin in hairy cell leukemia and other lymphoid malignancies has not been fully elucidated. Pentostatin is a potent transition state (tight binding) inhibitor of adenosine deaminase, an enzyme involved in purine metabolism. This enzyme appears to regulate intracellular adenosine concentrations via irreversible deamination of adenosine and deoxyadenosine. Although adenosine deaminase is widely distributed in mammalian tissues, highest levels are found in lymphoid tissue: levels in circulating T cells (particularly in T cell lymphoblastic leukemia) are higher than those in B cells. While the level of enzyme activity is low in healthy bone marrow, it is high in myeloid leukemic blast cells. ... Inhibition of adenosine deaminase by pentostatin results in intracellular accumulation of toxic levels of adenine deoxynucleotides (eg, deoxyadenosine triphosphate), which in the presence of deoxyadenosine can lead to cell death. Pentostatin alone, even in concentrations high enough to inhibit adenosine deaminase completely, is not cytotoxic to lymphoid cells cultured in the absence of cytotoxic nucleosides (eg, deoxyadenosine). Thus, unlike many other nucleoside-analog antineoplastic agents, the cytoxic effects of pentostatin do not appear to be attributable directly to the drug or its metabolites but instead appear to result indirectly from the effects of the substrates for adenosine deaminase (adenosine and deoxyadenosine) and/or their metabolites. Although elevated deoxyadenosine triphosphate concentrations in the cell can block DNA synthesis via inhibition of ribonucleotide reductase, the precise role of high deoxyadenosine triphosphate concentrations in pentostatin-induced cytotoxicity is controversial. Pentostatin also can inhibit RNA synthesis, cause DNA strand breaks, disrupt ATP-dependent cellular processes, and inhibit adenosylhomocysteinase (S-adenosylhomocysteine hydrolase), all of which also may contribute to the drug's lymphocytotoxic effects.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 633
The degree to which pentostatin inhibits adenosine deaminase varies among cell types, possibly because of differences in enzyme inhibitor dissociation constants in different cells as well as differences in cellular accumulation of the drug. There generally has been no clear relation between adenosine deaminase inhibition and pentostatin induced cytotoxicity in clinical studies. However, the cytotoxic and growth inhibitory effects of adenosine deaminase inhibition appear to be greater in T cells than in B cells. Although conflicting data exist, some evidence suggests that T cells accumulate more deoxyadenosine triphosphate than B cells and thus may be more susceptible to the effects of adenosine deaminase inhibition; deoxyadenosine triphosphate concentrations in B cells may be lower because these cells possess higher membrane associated ecto-5'-nucleotidase activity, which promotes the hydrolysis of higher phosphate compounds to more freely diffusible nucleosides. Differences in the sensitivity of B and T cells to pentostatin's effects also may be artifactual as a result of testing procedure variables (eg, cell source, culture media conditions). The time course of adenosine deaminase inhibition appears to differ in erythrocytes and lymphocytes and depends on the intrinsic activity of the enzyme in the cell as well as cell specific pharmacodynamics (eg, protein synthesis, rate of cellular proliferation). In some cells, inhibition by a single dose of pentostatin may persist for 1 week or longer. It is not known whether recovery from adenosine deaminase inhibition occurs as a result of slow efflux of pentostatin from the cell or regeneration of adenosine deaminase; however, recovery of blood adenosine deaminase activity may result from replenishment of enzyme from newly formed erythrocytes in that such recovery in animals has been reported to coincide with the life span of erythrocytes in circulation (eg, 40-60 days). ... Response to pentostatin varies according to the type and sensitivity of the neoplasm being treated. Conditions associated with relatively low adenosine deaminase activity (eg, hairy cell and chronic lymphocytic leukemias) manifest prolonged and complete adenosine deaminase inhibition in response to relatively low dosages of pentostatin, whereas conditions associated with high adenosine deaminase activity (eg, acute leukemias) are less sensitive to the drug, requiring higher doses that produce relatively incomplete inhibition of adenosine deaminase activity.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 633

8.9 Human Metabolite Information

8.9.1 Cellular Locations

Cytoplasm

9 Use and Manufacturing

9.1 Uses

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

9.1.1 Use Classification

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

9.2 Methods of Manufacturing

Produced by Streptomyces antibioticus.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 632

9.3 Formulations / Preparations

Parenteral: For injection, 10 mg, Nipent(R) (with mannitol 50 mg). Parke-Davis.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 637

10 Safety and Hazards

10.1 Hazards Identification

10.1.1 GHS Classification

Pictogram(s)
Acute Toxic
Signal
Danger
GHS Hazard Statements
H301 (97.5%): Toxic if swallowed [Danger Acute toxicity, oral]
Precautionary Statement Codes

P264, P270, P301+P316, P321, P330, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 40 reports by companies from 2 notifications to the ECHA C&L Inventory.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

10.1.2 Hazard Classes and Categories

Acute Tox. 3 (97.5%)

10.2 Regulatory Information

California Safe Cosmetics Program (CSCP) Reportable Ingredient

Hazard Traits - Developmental Toxicity

Authoritative List - Prop 65

Report - regardless of intended function of ingredient in the product

New Zealand EPA Inventory of Chemical Status
Imidazo4,5-d1,3diazepin-8-ol, 3-(2-deoxy-.beta.-D-erythro-pentofuranosyl)-3,4,7,8-tetrahydro-, (8R)-: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.

10.2.1 FDA Requirements

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).
21 CFR 200-299, 300-499, 820, and 860 (4/1/91)
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl pentostatin, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act.
DHHS/FDA; Approved Drug Products with Therapeutic Equivalence Evaluations 12th edition p.3-217 (1992)

11 Toxicity

11.1 Toxicological Information

11.1.1 Toxicity Summary

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).

11.1.2 Hepatotoxicity

In clinical trials, serum enzymes elevations occurred in up to 25% of patients receiving pentostatin, but the abnormalities were generally mild and transient and rarely required dose modification. Clinically apparent liver injury from pentostatin is rare, but striking instances of severe liver injury leading rapidly to multiorgan failure and death have been described both in adults and children. The time to onset varied from a few days to six months. The possible role of shock, ischemia, opportunistic infections and sepsis in these cases has not always been well defined. Both hepatocellular and cholestatic patterns of enzyme elevations have been described. Immunoallergic features and autoantibodies were not typical.

Likelihood score: D (possible rare cause of clinically apparent liver disease).

11.1.3 Drug Induced Liver Injury

Compound
pentostatin
DILI Annotation
Most-DILI-Concern
Severity Grade
3
Label Section
Box warning
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

11.1.4 Carcinogen Classification

Carcinogen Classification
No indication of carcinogenicity to humans (not listed by IARC).

11.1.5 Health Effects

Antibiotic resistance

11.1.6 Exposure Routes

Not absorbed orally, crosses blood brain barrier.

11.1.7 Symptoms

Side effects include lethargy, rash, fatigue, nausea and myelosuppression.

11.1.8 Acute Effects

11.1.9 Toxicity Data

ToxicityData
Mouse(iv): LD50 122 mg/kg
National Technical Information Service, PB84-211424
LD50=128 mg/kg (mouse)

11.1.10 Interactions

Limited data suggest that concomitant therapy with pentostatin (4 mg/sq m every 2 weeks) and fludarabine (principally 10 mg/sq m daily for 4 days at 28 day intervals), a synthetic purine nucleoside, may be associated with severe and/or fatal pulmonary toxicity (eg, pneumonitis). In one study, 4 of 6 patients receiving the drugs concomitantly for treatment of refractory chronic lymphocytic leukemia reportedly developed such toxicity.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 636
Although therapy with either pentostatin or allopurinol alone has been associated with the development of skin rash, limited evidence suggests that concomitant use of the drugs, compared with pentostatin therapy alone, in patients with refractory hairy cell leukemia is not associated with an increased incidence of rash. However, other toxicities, including abnormalities in renal or hepatic function, have been observed in a few patients receiving concomitant pentostatin and allopurinol. ... One patient reportedly developed a fatal hypersensitivity vasculitis while receiving pentostatin and allopurinol concurrently; however, a causal relationship to the drugs has not been established.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 636
Pentostatin inhibits the degradation of vidarabine and enhances its cytotoxicity in cell culture and in animals with experimentally induced leukemia. In addition, limited data in patients with acute leukemia suggest that combined therapy with the drugs may be associated with increased plasma vidarabine concentrations and/or half-life and greater toxicity compared with pentostatin therapy alone. Although improvement and/or remission has been reported in a few patients with acute T cell lymphoblastic leukemia who received vidarabine and pentostatin concomitantly.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 636

11.1.11 Antidote and Emergency Treatment

No specific antidote for pentostatin overdosage is known. Administration of pentostatin in dosages higher than those currently recommended (20-50 mg/sq m over 5 days as compared with 4 mg/sq m every other week, respectively) has been associated with severe renal, hepatic, pulmonary, and CNS toxicity, which was unpredictable and occasionally fatal. In case of overdosage, management should include discontinuance of the drug and initiation of supportive measures appropriate to the type of toxicity observed.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 636

11.1.12 Human Toxicity Excerpts

The frequency and severity of pentostatin-induced myelosuppression appear to be related principally to the underlying disease type and tumor mass. In patients whose malignancy includes bone marrow involvement (eg; in hairy cell leukemia), myelosuppression associated with the drug generally is more frequent and more severe than in those without such involvement (eg; in mycosis fungoides); thus, even at low dosages, substantial myelosuppression can occur in certain patients. ... Leukopenia, anemia, thrombocytopenia, and hemorrhage have been reported in 60, 35, 32%, and 3-10%, respectively, of patients receiving pentostatin therapy for the treatment of hairy cell leukemia. Myelosuppression appears to be particularly likely during the first several courses of therapy with the drug. Assessing the myelosuppressive effect of pentostatin can be difficult because many patients with hairy cell leukemia have preexisting disease related myelosuppression. As response to pentostatin therapy occurs, a corresponding improvement in marrow status also may be observed, and each subsequent treatment course may be associated with a lesser degree of marrow suppression. ... Adverse hematologic effects reported in less than 3% of patients receiving pentostatin and for which a causal relationship has not been established include abnormal erythrocytes, hemolysis, eosinophilia, leukocytosis, pancytopenia, splenomegaly,thrombocythemia, lymphoma like reaction, and unspecified hematologic disorder.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 635
Pentostatin appears to cause dosage schedule dependent nervous system toxicity, even in patients with normal renal function. Increasing lethargy with successive doses of pentostatin has been reported in some patients receiving the drug weekly, and most clinicians recommend that the drug generally not be administered more frequently than every 2 weeks. If weekly therapy is used, some clinicians recommend that no more than 3 successive weekly doses be given. It has been suggested that CNS effects may be related to intracerebral accumulation of deoxyadenosine and/or adenosine; such cumulative toxicity has not been reported with the currently recommended every other week dosage schedule for pentostatin. Pentostatin-induced nervous system toxicity (eg; seizures, coma) rarely can be fatal.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 635
Fatigue, pain, headache, and unspecified CNS disorder have been reported in 29, 20, 13, and 11%, respectively, of patients receiving pentostatin therapy. Adverse nervous system effects reported in 3-10% of patients receiving the drug include abnormal thinking (eg; mental slowing), anxiety, confusion, depression, dizziness, insomnia, nervousness, paresthesia, and somnolence. Abnormal dreams, abnormal gait, agitation, amnesia, apathy, ataxia, CNS depression, coma, decreased libido, decreased reflexes, depersonalization, emotional lability, facial paralysis, hyperesthesia or hypoesthesia, hypertonia, incoordination, neuropathy, parosmia, postural dizziness, seizures, stupor, taste perversion, tremor, and vertigo have been reported in less than 3% of patients receiving pentostatin; however, a causal relationship to the drug has not been established. Multiple, small, nonhemorrhagic cerebral infarcts were found in one patient receiving the currently recommended dosage of pentostatin who developed a change in mental status and arm weakness; however, the CNS deficit subsequently improved, and the role of pentostatin in the development of these infarcts is unclear.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 635
Adverse ocular and otic effects reported in 3-10% of patients receiving pentostatin include abnormal vision, keratoconjunctivitis, otic pain, and ocular pain. Blepharitis, cataract formation, deafness, diplopia, exophthalmos, lacrimation disorder, optic neuritis, otitis media, retinal detachment, and tinnitus have been reported in less than 3% of patients receiving pentostatin; however, a causal relationship to the drug has not been established. One patient receiving the drug for hairy cell leukemia reportedly developed unilateral uveitis with vision loss.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 635
For more Human Toxicity Excerpts (Complete) data for PENTOSTATIN (17 total), please visit the HSDB record page.

11.1.13 Non-Human Toxicity Excerpts

There was no evidence of mutagenicity when pentostatin was tested in several strains of Salmonella typhimurium; however, when tested in strain TA-100 with or without metabolic activation, a reproducible mutagenic response was observed. The mutagenic response was approximately two fold higher than the standard at the maximum drug concentration tested (10 mg/plate). The commercially available formulation of pentostatin was clastogenic in vivo when tested in the mouse bone marrow micronucleus assay at concentrations of 20, 120, and 240 mg/kg. Pentostatin with or without metabolic activation was not mutagenic nor did it increase chromosomal aberrations in Chinese hamster lung cells exposed to the drug at concentrations of 1-3 mg/ml for 3 hrs.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 636
Pentostatin produced both maternal and fetal (teratogenic) toxicity in animal studies at dosages approximating those currently recommended in humans.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 636
Mild seminiferous tubular degeneration was observed in animals during an iv toxicity study of the drug at doses of 1 and 4 mg/kg.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 636

11.1.14 Protein Binding

4%

12 Associated Disorders and Diseases

13 Literature

13.1 Consolidated References

13.2 NLM Curated PubMed Citations

13.3 Springer Nature References

13.4 Thieme References

13.5 Chemical Co-Occurrences in Literature

13.6 Chemical-Gene Co-Occurrences in Literature

13.7 Chemical-Disease Co-Occurrences in Literature

14 Patents

14.1 Depositor-Supplied Patent Identifiers

14.2 WIPO PATENTSCOPE

14.3 Chemical Co-Occurrences in Patents

14.4 Chemical-Disease Co-Occurrences in Patents

14.5 Chemical-Gene Co-Occurrences in Patents

15 Interactions and Pathways

15.1 Protein Bound 3D Structures

15.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

15.2 Chemical-Target Interactions

15.3 Drug-Drug Interactions

16 Biological Test Results

16.1 BioAssay Results

17 Taxonomy

The LOTUS Initiative for Open Natural Products Research: frozen dataset union wikidata (with metadata) | DOI:10.5281/zenodo.5794106

18 Classification

18.1 MeSH Tree

18.2 NCI Thesaurus Tree

18.3 ChEBI Ontology

18.4 KEGG: USP

18.5 KEGG: ATC

18.6 KEGG: Target-based Classification of Drugs

18.7 KEGG: Drug Groups

18.8 KEGG: Drug Classes

18.9 WHO ATC Classification System

18.10 FDA Pharm Classes

18.11 ChemIDplus

18.12 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

18.13 ChEMBL Target Tree

18.14 UN GHS Classification

18.15 NORMAN Suspect List Exchange Classification

18.16 EPA DSSTox Classification

18.17 The Natural Products Atlas Classification

18.18 LOTUS Tree

18.19 MolGenie Organic Chemistry Ontology

19 Information Sources

  1. BindingDB
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    https://www.bindingdb.org/rwd/bind/info.jsp
    (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
    https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=22925
  2. ChEMBL
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    http://www.ebi.ac.uk/Information/termsofuse.html
  3. Comparative Toxicogenomics Database (CTD)
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    http://ctdbase.org/about/legal.jsp
  4. Drug Gene Interaction database (DGIdb)
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    http://www.dgidb.org/downloads
  5. DrugBank
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    https://www.drugbank.ca/legal/terms_of_use
  6. IUPHAR/BPS Guide to PHARMACOLOGY
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  10. ChEBI
  11. FDA Pharm Classes
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
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    Imidazo4,5-d1,3diazepin-8-ol, 3-(2-deoxy-.beta.-D-erythro-pentofuranosyl)-3,4,7,8-tetrahydro-, (8R)-
    https://www.epa.govt.nz/industry-areas/hazardous-substances/guidance-for-importers-and-manufacturers/hazardous-substances-databases/
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    http://www.hmdb.ca/citing
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    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
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  28. NCI Investigational Drugs
  29. Drugs@FDA
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  30. EU Clinical Trials Register
  31. FDA Orange Book
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    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
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  39. NORMAN Suspect List Exchange
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    https://creativecommons.org/licenses/by/4.0/
    Pentostatin
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    https://www.norman-network.com/nds/SLE/
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    LICENSE
    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
    Adenosine Deaminase Inhibitors
    https://www.ncbi.nlm.nih.gov/mesh/68058892
  50. PubChem
  51. GHS Classification (UNECE)
  52. The Natural Products Atlas
    LICENSE
    The Natural Products Atlas is licensed under a Creative Commons Attribution 4.0 International License.
    https://www.npatlas.org/terms
    The Natural Products Atlas Classification
    https://www.npatlas.org/
  53. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  54. PATENTSCOPE (WIPO)
  55. NCBI
CONTENTS