Identification

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Name
Bendazac
Accession Number
DB13501
Type
Small Molecule
Groups
Approved, Withdrawn
Description

Bendazac is an oxyacetic acid 1,2. Despite possessing anti-inflammatory, anti-necrotic, choleretic, and anti-lipidemic characteristics, most research has revolved around studying and demonstrating the agent's principal action in inhibiting the denaturation of proteins - an effect that has primarily proven useful in managing and delaying the progression of ocular cataracts 1,1. Bendazac, however, has since been withdrawn or discontinued in various international regions due to its capability or risk for eliciting hepatotoxicity 4,5,6,10 in patients although a small handful of regions may continue to have the medication available for purchase and use either as a topical anti-inflammatory/analgesic cream or eye drop formulation.

Structure
Thumb
Synonyms
  • bendazaco
Categories
UNII
G4AG71204O
CAS number
20187-55-7
Weight
Average: 282.299
Monoisotopic: 282.100442319
Chemical Formula
C16H14N2O3
InChI Key
BYFMCKSPFYVMOU-UHFFFAOYSA-N
InChI
InChI=1S/C16H14N2O3/c19-15(20)11-21-16-13-8-4-5-9-14(13)18(17-16)10-12-6-2-1-3-7-12/h1-9H,10-11H2,(H,19,20)
IUPAC Name
2-[(1-benzyl-1H-indazol-3-yl)oxy]acetic acid
SMILES
OC(=O)COC1=NN(CC2=CC=CC=C2)C2=CC=CC=C12

Pharmacology

Indication

Prior to the withdrawal of bendazac from various international regions of use due to concerns for hepatotoxicity 4,5,6,10 the chemical had demonstrated potential usefulness predominantly as the prescription medication bendazac lysine for the indication of managing the level of vision in patients with mild to moderate cataracts to facilitate delaying the need for surgical intervention 1,2,3.

Elsewhere bendazac may still be available in a limited capacity as a non-prescription topical cream product for treating conditions like local pain, inflammation, dermatitis, eczema, pruritis, hives, insect bites, burns, erythema, and others 11 - although such products may also be facing general discontinuation 12.

Associated Conditions
Pharmacodynamics

Bendazac principally demonstrates an antidenaturant action on proteins 1,2. This effect has been shown to inhibit the denaturation of various proteins like ocular lens proteins by heat, ultraviolet radiation, free radicals, and other chemicals 1,2. The medication may be administered to patients via a number of different formulations, including orally as the lysine salt, as eye drops, or even topical applications for the skin 1,2.

Some preliminary studies have suggested that an apparent improvement of the blood-retinal barrier had been observed in diabetic patients using bendazac lysine 500 mg three times a day for three to six months 2. Moreover, the use of topical bendazac has also been shown to demonstrate anti-inflammatory effects in animal models and clinical studies to effectively treat varied dermatoses, especially those involving a necrotic component 2.

Additionally, bendazac has also demonstrated choleretic and antilipidaemic activities that have resulted in substantial reductions in beta/alpha lipoprotein ratio, and total lipid, total cholesterol, and triglyceride levels in patients with dyslipidaemia using oral bendazac lysine 500 mg three times daily 1,2. The medication has also elicited the inhibition of phytohaemagglutinin induced lymphocyte transformation in vitro 1,2.

Mechanism of action

Bendazac seems to elicit an anticataract action by inhibiting the denaturation of ocular lens proteins, although the precise mechanisms by which this action occurs has not yet been formally elucidated - despite there being many proposed mechanisms 1,2. In particular, the denaturation of lens proteins may in part be prevented by inhibiting the binding of certain chemicals like cyanates or sugars and 5-hydroxybendazac - the major metabolite of bendazac - has been shown to be capable of inhibiting the glycosylation of lens proteins by sugars like galactose or glucose-6-phosphate in a dose-dependent manner 2. Moreover, the apparent ability for administered bendazac to elicit free radical scavenger activities due to interactions with protein molecules suggests that the medication may also be able to prevent the oxidation of lens proteins by free radicals in the development of cataracts 1,2. Furthermore, bendazac may also be capable of reducing the sulfhydryl group oxidation of lens proteins by the saliva, serum, or urine from patients with cataracts following single dose administration and reduce biological liquid oxidant activity (BLOA) in doing so 2.

Otherwise, it is believed that bendazac also possesses non-steroidal anti-inflammatory actions, as well as analgesic, antipyretic, and platelet-inhibitory effects 13,9 These effects may be accounted for in part by the substance's capability to inhibit prostaglandin synthesis by inhibiting cyclooxygenase activity in converting arachidonic acid to cyclic endoperoxides - the precursors of prostaglandins 13,9.

TargetActionsOrganism
UFree radicals
blocker
Humans
UProstaglandin G/H synthase 1Not AvailableHumans
UProstaglandin G/H synthase 2Not AvailableHumans
Absorption

Administered as its lysine salt, a 500 mg oral tablet of bendazac is well absorbed into the human body with maximum plasma concentrations Cmax ranging from 35 to 55 mg/L being attained within 0.5 to 1 hour in healthy volunteers after oral administration of a single 500 mg dose 1,2.

Volume of distribution

The volume of distribution documented for bendazac is 0.16 L/kg 1,2.

Protein binding

Bendazac is >99% highly bound to plasma albumin protein in healthy subjects 1,2.

Metabolism

Bendazac is largely eliminated by metabolism, where more than 60% of an administered dose is excreted in the urine as the hydroxylated primary metabolite 5-hydroxybendazac and its glucuronide 1,2,7 while up to approximately 15% of a bendazac dose is also excreted in the urine unchanged and as a glucuronide 1,2. Unfortunately, there is little data available regarding the specific enzymes responsible for bendazac's metabolism 8.

Route of elimination

About 60% of a dose of bendazac is eliminated via the urine as its primary metabolite, 5-hydroxybendazac 1,2. Approximately 15% of a dose is eliminated as unchanged drug and bendazac glucuronide in the urine as well1,2.

Half life

The plasma elimination half-life recorded for bendazac is given as 1.7 to 5.2 hours, with a mean of 3.5 hours 1,2.

Clearance

The plasma clearance recorded for bendazac is given as 0.018 to 0.054 L/h/kg with a mean of 0.033 L/h/kg 1,2.

Toxicity

A number of case reports demonstrating the capability for bendazac oral and eye drop therapy to cause potential hepatotoxicity via increases in serum transaminases in patients have been documented 4,5,2. Moreover, bendazac has also since been discontinued or withdrawn in various international regions due to the possibility and risk of eliciting hepatotoxicity in patients 6,10.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
(R)-warfarinThe risk or severity of bleeding and hemorrhage can be increased when Bendazac is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding and hemorrhage can be increased when Bendazac is combined with (S)-Warfarin.
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidThe risk or severity of hypertension can be increased when 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid is combined with Bendazac.
1-benzylimidazoleThe risk or severity of hypertension can be increased when 1-benzylimidazole is combined with Bendazac.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of hypertension can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Bendazac.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of hypertension can be increased when Bendazac is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of hypertension can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Bendazac.
4-hydroxycoumarinThe risk or severity of bleeding and hemorrhage can be increased when Bendazac is combined with 4-hydroxycoumarin.
4-MethoxyamphetamineThe risk or severity of hypertension can be increased when 4-Methoxyamphetamine is combined with Bendazac.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of hypertension can be increased when Bendazac is combined with 5-methoxy-N,N-dimethyltryptamine.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

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Food Interactions
Not Available

References

Synthesis Reference

Bendazac synthesis: BE 699226 (https://worldwide.espacenet.com/publicationDetails/biblio?CC=BE&NR=699226&KC=&FT=E&locale=en_EP), and U.S. Patent US3470194A (https://patents.google.com/patent/US3470194)

General References
  1. Rovei V, Escourrou J, Campistron G, Ego D, Thiola A, Ribet A, Houin G: The pharmacokinetics of bendazac-lysine and 5-hydroxybendazac, its main metabolite, in patients with hepatic cirrhosis. Eur J Clin Pharmacol. 1988;35(4):391-6. [PubMed:3197747]
  2. Balfour JA, Clissold SP: Bendazac lysine. A review of its pharmacological properties and therapeutic potential in the management of cataracts. Drugs. 1990 Apr;39(4):575-96. doi: 10.2165/00003495-199039040-00007. [PubMed:2190795]
  3. Soldo L, Ruggieri A, Milanese C, Pinza M, Guglielmotti A: Bendazac lysine inhibition of human lens epithelial cell adhesion to polymethylmethacrylate intraocular lenses. Ophthalmic Res. 2004 May-Jun;36(3):145-50. doi: 10.1159/000077327. [PubMed:15103205]
  4. Prieto de Paula JM, Rodriguez Rodriguez E, Villamandos Nicas V, Sanz de la Fuente H, Prada Minguez A, del Portillo Rubi A: [Bendazac hepatotoxicity: analysis of 16 cases]. Rev Clin Esp. 1995 Jun;195(6):387-9. [PubMed:7644786]
  5. Alcalde M, Garcia-Diaz M, Najarro F, Donoso MS, Cebria L, Pascasio JM: Hepatotoxicity due to lysine salt of bendazac. Scand J Gastroenterol. 1996 Feb;31(2):206-8. [PubMed:8658045]
  6. Need AC, Motulsky AG, Goldstein DB: Priorities and standards in pharmacogenetic research. Nat Genet. 2005 Jul;37(7):671-81. doi: 10.1038/ng1593. [PubMed:15990888]
  7. Lewis BS, Harding JJ: The major metabolite of bendazac inhibits the glycosylation of soluble lens proteins: a possible mechanism for a delay in cataractogenesis. Exp Eye Res. 1988 Aug;47(2):217-25. [PubMed:3409993]
  8. Yu K, Geng X, Chen M, Zhang J, Wang B, Ilic K, Tong W: High daily dose and being a substrate of cytochrome P450 enzymes are two important predictors of drug-induced liver injury. Drug Metab Dispos. 2014 Apr;42(4):744-50. doi: 10.1124/dmd.113.056267. Epub 2014 Jan 24. [PubMed:24464804]
  9. Alison Brayfield (2017). Martindale the Complete Drug Reference - Volume A (39th ed.). Pharmaceutical Press. [ISBN:9780857113092]
  10. Pre-Clinical Assessment of the Potential Intrinsic Hepatotoxicity of Candidate Drugs [Link]
  11. eFarma.com: Bendazac Cream Product Page [Link]
  12. Iwaki Seiyaku Co.Ltd.: Bendazac Ointment 3% Discontinued Product Page [Link]
  13. Pharmacompass: Bendazac Profile [Link]
External Links
ChemSpider
2223
ChEBI
31257
ChEMBL
CHEMBL1089221
Wikipedia
Bendazac
ATC Codes
M02AA11 — BendazacS01BC07 — Bendazac
MSDS
Download (82.9 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.103 mg/mLALOGPS
logP2.89ALOGPS
logP3.06ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)3.66ChemAxon
pKa (Strongest Basic)0.35ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area64.35 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity88.76 m3·mol-1ChemAxon
Polarizability28.97 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

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 indazoles. These are compounds containing an indazole, which is structurally characterized by a pyrazole fused to a benzene.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzopyrazoles
Sub Class
Indazoles
Direct Parent
Indazoles
Alternative Parents
Alkyl aryl ethers / Benzene and substituted derivatives / Pyrazoles / Heteroaromatic compounds / Monocarboxylic acids and derivatives / Carboxylic acids / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organic oxides
show 2 more
Substituents
Benzopyrazole / Indazole / Alkyl aryl ether / Monocyclic benzene moiety / Benzenoid / Azole / Heteroaromatic compound / Pyrazole / Carboxylic acid derivative / Azacycle
show 12 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
monocarboxylic acid, indazoles (CHEBI:31257)

Targets

1. Free radicals
Kind
Group
Organism
Humans
Pharmacological action
Unknown
Actions
Blocker
References
  1. Rovei V, Escourrou J, Campistron G, Ego D, Thiola A, Ribet A, Houin G: The pharmacokinetics of bendazac-lysine and 5-hydroxybendazac, its main metabolite, in patients with hepatic cirrhosis. Eur J Clin Pharmacol. 1988;35(4):391-6. [PubMed:3197747]
  2. Balfour JA, Clissold SP: Bendazac lysine. A review of its pharmacological properties and therapeutic potential in the management of cataracts. Drugs. 1990 Apr;39(4):575-96. doi: 10.2165/00003495-199039040-00007. [PubMed:2190795]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Prostaglandin-endoperoxide synthase activity
Specific Function
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gas...
Gene Name
PTGS1
Uniprot ID
P23219
Uniprot Name
Prostaglandin G/H synthase 1
Molecular Weight
68685.82 Da
References
  1. Alison Brayfield (2017). Martindale the Complete Drug Reference - Volume A (39th ed.). Pharmaceutical Press. [ISBN:9780857113092]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Prostaglandin-endoperoxide synthase activity
Specific Function
Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. Constitutively expressed in some tissues in physiological conditions, such as the endothelium, kidney and...
Gene Name
PTGS2
Uniprot ID
P35354
Uniprot Name
Prostaglandin G/H synthase 2
Molecular Weight
68995.625 Da
References
  1. Alison Brayfield (2017). Martindale the Complete Drug Reference - Volume A (39th ed.). Pharmaceutical Press. [ISBN:9780857113092]

Drug created on June 23, 2017 14:43 / Updated on December 02, 2019 09:59