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Identification
- Summary
Zucapsaicin is a topical analgesic used as an adjunct to relieve severe pain of osteoarthritis of the knee in selected adult patients.
- Generic Name
- Zucapsaicin
- DrugBank Accession Number
- DB09120
- Background
Zucapsaicin, the cis-isomer of capsaicin, is a topical analgesic used to treat osteoarthritis of the knee and other neuropathic pain. It is a modulator of transient receptor potential cation channel subfamily V member 1 (TRPV-1), also known as the vanilloid or capsaicin receptor 1, that reduces pain and improves articular functions. Zucapsaicin has also been evaluated for the management of several conditions manifested by chronic nerve pain. These conditions include herpes simplex (HSV) infections, cluster headaches, migraine, and osteoarthritis of the knee. Zucapsaicin was approved by the Health Canada in 2010 as topical cream marketed under the brand name Zuacta but currently not FDA-approved.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Zucapsaicin (DB09120)
- Weight
- Average: 305.4119
Monoisotopic: 305.199093735 - Chemical Formula
- C18H27NO3
- Synonyms
- (Z)-Capsaicin
- cis-Capsaicin
- Civamide
- Zucapsaicin
Pharmacology
- Indication
Indicated to be used in conjunction with oral COX-2 inhibitors or NSAIDs for the relief of severe pain in adult patients with osteoarthritis of the knee, not controlled with oral COX-2 inhibitors or NSAIDs alone, for a duration of no more than three months.
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Adjunct therapy in treatment of Severe pain •••••••••••• ••••• Adjunct therapy in treatment of Severe pain •••••••••••• ••••• Used in combination to treat Severe pain •••••••••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Zucapsaicin mediates an antinociceptive action via acting as an agonist at TRPV1. TRPV1 play an important physiological role of transducing chemical, mechanical and thermal stimuli as well as pain transduction, and participate in pain modulation and perception. They are mainly distributed in C sensory nerve fibers as well as Aẟ fibers to transmit sensory information involving inflammatory and neuropathic pain, and activation of these channels releasesomatostatin, calcitonin gene-related peptide (CGRP) and other neuropeptides (neurokinin A, kassinin), leading to neurogenic inflammation 1. Zucapsaicin is also reported to affect the peptidergic afferent neurons via a desensitization mechanism to decrease the levels of dorsal root ganglia and sciatic calcitonin gene-related peptide (CGRP) and substance P (SP) 5.
- Mechanism of action
Zucapsaicin excites and desensitizes C-fibers via agonist at TRPV1 on nociceptive neurons. It binds to intracellular sites and initially stimulates the channels, causing burning sensation. Activation of TRPV1 results in calcium influx and sodium, which leads to cell depolarization. Hypersensitization by zucapsaicin is then followed by reduced sensitivity and persistent desensitization (tachyphylaxis) of the channels via various pathways. Densentiziation is thought to be dependent on intraceullar levels of calcium 4. Decreased TRPV1 channel action and release of inflammatory neuropeptides induces an analgesic effect, and pain relief 1,2. Zucapsaicin activates calcineurin and calcium-dependent protein kinase C isoforms which results in phosphorylation of TRPV1. Phosphorylation of TRPV1 enhances reponsivity to zucapsaicin by potentiating capsaicin- or proton-evoked responses and reducing the temperature threshold for TRPV1 activation 4. Studies suggest that zucapsaicin is involved in activation of phospholipase C with the subsequent phosphatidylinositol 4,5-biphosphate (PIP2) hydrolysis, which results in TRPV1 inactivation 4. Tachyphylaxis or persistent desensitization is reversible, and involves the downregulation of proalgesic substances (such as SP) and upregulation of analgesic peptides 1.
Target Actions Organism ATransient receptor potential cation channel subfamily V member 1 agonistactivatorHumans - Absorption
Zucapsaicin displays low systemic absorption and localizes at the area of application. In animal studies, systemic absorption is 0.075% 5.
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
In vitro studies demonstrates weak to moderate inhibitiory effects on various cytochrome P450 enzymes, although not clinically significant due to low systemic absorption.
- Route of elimination
In rat studies, zucapsaicin and its metabolites are slowly excreted into urine and feces (up to 2/3), with minimal elimination via exhalation following dermal administration 5.
- Half-life
In rats, the elimination half life of zucapsaicin and its metabolites is approximately 7 to 11 hours 5.
- Clearance
Not Available
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Most common adverse effects involved application site reactions such as transient burning and warm sensation. Other adverse effects observed in clinical trials are eye irritation, arthralgia, aggravated osteoarthritis, burning sensation, headache, cough and sneezing. Oral LD50 in mouse is >87.5 mg/kg in male and <60 mg/kg in females. Oral LD50 in rats is >90 mg/kg in males and >60 mg/kg in females.5
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareBelzutifan The serum concentration of Belzutifan can be increased when it is combined with Zucapsaicin. Clobazam The serum concentration of Clobazam can be increased when it is combined with Zucapsaicin. Fezolinetant The serum concentration of Fezolinetant can be increased when it is combined with Zucapsaicin. Mavacamten The serum concentration of Mavacamten can be increased when it is combined with Zucapsaicin. Pirfenidone The metabolism of Pirfenidone can be decreased when combined with Zucapsaicin. - Food Interactions
- No interactions found.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- International/Other Brands
- Civanex
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Zuacta Cream 0.075 % w/w Topical Sanofi Aventis 2011-08-24 2020-07-17 Canada 
Categories
- ATC Codes
- M02AB02 — Zucapsaicin
- Drug Categories
- Alkaloids
- Alkenes
- Alkynes
- Amides
- Analgesics
- Benzene Derivatives
- Capsaicin and Similar Agents
- Catechols
- Cytochrome P-450 CYP1A2 Inhibitors
- Cytochrome P-450 CYP1A2 Inhibitors (moderate)
- Cytochrome P-450 CYP2C19 Inhibitors
- Cytochrome P-450 CYP2C19 Inhibitors (moderate)
- Cytochrome P-450 CYP2C9 Inhibitors
- Cytochrome P-450 CYP2C9 Inhibitors (weak)
- Cytochrome P-450 CYP2E1 Inhibitors
- Cytochrome P-450 CYP2E1 Inhibitors (weak)
- Cytochrome P-450 Enzyme Inhibitors
- Fatty Acids
- Fatty Acids, Monounsaturated
- Fatty Acids, Unsaturated
- Hydrocarbons, Acyclic
- Lipids
- Musculo-Skeletal System
- Other Nonsteroidal Anti-inflammatory Agents
- Phenols
- Polyunsaturated Alkamides
- Solanaceous Alkaloids
- Topical Products for Joint and Muscular Pain
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as methoxyphenols. These are compounds containing a methoxy group attached to the benzene ring of a phenol moiety.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Phenols
- Sub Class
- Methoxyphenols
- Direct Parent
- Methoxyphenols
- Alternative Parents
- Phenoxy compounds / Methoxybenzenes / Anisoles / Alkyl aryl ethers / 1-hydroxy-2-unsubstituted benzenoids / N-acyl amines / Secondary carboxylic acid amides / Organopnictogen compounds / Organonitrogen compounds / Organic oxides show 2 more
- Substituents
- 1-hydroxy-2-unsubstituted benzenoid / Alkyl aryl ether / Anisole / Aromatic homomonocyclic compound / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Ether / Fatty acyl / Fatty amide show 14 more
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 15OX67P384
- CAS number
- 25775-90-0
- InChI Key
- YKPUWZUDDOIDPM-VURMDHGXSA-N
- InChI
- InChI=1S/C18H27NO3/c1-14(2)8-6-4-5-7-9-18(21)19-13-15-10-11-16(20)17(12-15)22-3/h6,8,10-12,14,20H,4-5,7,9,13H2,1-3H3,(H,19,21)/b8-6-
- IUPAC Name
- (6Z)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide
- SMILES
- COC1=C(O)C=CC(CNC(=O)CCCC\C=C/C(C)C)=C1
References
- Synthesis Reference
- Gannett PM, Nagel DL, Reilly PJ, Lawson T, Sharpe J, Toth B: The Capsaicinoids: Their Separation, Synthesis, and Mutagenicity. J. Org. Chem., 1988, 53 (5), pp 1064–1071.
- Kaga H, Miura M, Orito K: A facile procedure for synthesis of capsaicin. J. Org. Chem., 1989, 54 (14), pp 3477–3478.
- General References
- Salat K, Jakubowska A, Kulig K: Zucapsaicin for the treatment of neuropathic pain. Expert Opin Investig Drugs. 2014 Oct;23(10):1433-40. doi: 10.1517/13543784.2014.956079. Epub 2014 Aug 29. [Article]
- Derry S, Lloyd R, Moore RA, McQuay HJ: Topical capsaicin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD007393. doi: 10.1002/14651858.CD007393.pub2. [Article]
- Studer M, McNaughton PA: Modulation of single-channel properties of TRPV1 by phosphorylation. J Physiol. 2010 Oct 1;588(Pt 19):3743-56. doi: 10.1113/jphysiol.2010.190611. Epub 2010 Aug 6. [Article]
- Rosenbaum T, Simon SA: TRPV1 Receptors and Signal Transduction . [Article]
- Health Canada Product Monograph: Zuacta (zucapsaicin) topical cream [Link]
- External Links
- PubChem Compound
- 1548942
- PubChem Substance
- 310265037
- ChemSpider
- 1265956
- BindingDB
- 50519720
- ChEBI
- 135952
- ChEMBL
- CHEMBL313971
- ZINC
- ZINC000004468952
- Wikipedia
- Zucapsaicin
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data3 Completed Treatment Episodic Cluster Headache 2 somestatus stop reason just information to hide 3 Completed Treatment Osteoarthritis of the Knee 2 somestatus stop reason just information to hide 3 Not Yet Recruiting Prevention Episodic Cluster Headache 1 somestatus stop reason just information to hide 2 Completed Treatment Dry Eyes 1 somestatus stop reason just information to hide 2 Completed Treatment Postherpetic Neuralgia 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Cream Topical 0.075 % w/w - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 71.5-74.5 Product monograph water solubility Insoluble Product monograph - Predicted Properties
Property Value Source Water Solubility 0.00841 mg/mL ALOGPS logP 3.8 ALOGPS logP 3.75 Chemaxon logS -4.6 ALOGPS pKa (Strongest Acidic) 9.93 Chemaxon pKa (Strongest Basic) -1.4 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 58.56 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 90.32 m3·mol-1 Chemaxon Polarizability 35.34 Å3 Chemaxon Number of Rings 1 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 201.799676 predictedDarkChem Lite v0.1.0 [M-H]- 180.55632 predictedDeepCCS 1.0 (2019) [M+H]+ 202.371676 predictedDarkChem Lite v0.1.0 [M+H]+ 183.1008 predictedDeepCCS 1.0 (2019) [M+Na]+ 201.807676 predictedDarkChem Lite v0.1.0 [M+Na]+ 190.95708 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- AgonistActivator
- General Function
- Ligand-activated non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli. Seems to mediate proton influx and may be involved in intracellular acidosis in nociceptive neurons. Involved in mediation of inflammatory pain and hyperalgesia. Sensitized by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases, which involves PKC isozymes and PCL. Activation by vanilloids, like capsaicin, and temperatures higher than 42 degrees Celsius, exhibits a time- and Ca(2+)-dependent outward rectification, followed by a long-lasting refractory state. Mild extracellular acidic pH (6.5) potentiates channel activation by noxious heat and vanilloids, whereas acidic conditions (pH <6) directly activate the channel. Can be activated by endogenous compounds, including 12-hydroperoxytetraenoic acid and bradykinin. Acts as ionotropic endocannabinoid receptor with central neuromodulatory effects. Triggers a form of long-term depression (TRPV1-LTD) mediated by the endocannabinoid anandamine in the hippocampus and nucleus accumbens by affecting AMPA receptors endocytosis
- Specific Function
- ATP binding
- Gene Name
- TRPV1
- Uniprot ID
- Q8NER1
- Uniprot Name
- Transient receptor potential cation channel subfamily V member 1
- Molecular Weight
- 94955.33 Da
References
- Yang F, Xiao X, Cheng W, Yang W, Yu P, Song Z, Yarov-Yarovoy V, Zheng J: Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel. Nat Chem Biol. 2015 Jul;11(7):518-24. doi: 10.1038/nchembio.1835. Epub 2015 Jun 8. [Article]
- Smutzer G, Devassy RK: Integrating TRPV1 Receptor Function with Capsaicin Psychophysics. Adv Pharmacol Sci. 2016;2016:1512457. doi: 10.1155/2016/1512457. Epub 2016 Jan 14. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable)
- Specific Function
- aromatase activity
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58406.915 Da
References
- Health Canada Product Monograph: Zuacta (zucapsaicin) topical cream [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:19965576, PubMed:20972997). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307)
- Specific Function
- (R)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55944.565 Da
References
- Zuacta Monograph [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Enzyme action is based on in vitro data. There is limited information in the literature supporting this enzyme action, however, the monograph indicates this enzyme action.
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599, PubMed:7574697, PubMed:9435160, PubMed:9866708). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:15766564, PubMed:19965576, PubMed:7574697, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9435160, PubMed:9866708). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031)
- Specific Function
- (R)-limonene 6-monooxygenase activity
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- Zuacta Monograph [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of fatty acids (PubMed:10553002, PubMed:18577768). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10553002, PubMed:18577768). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates fatty acids specifically at the omega-1 position displaying the highest catalytic activity for saturated fatty acids (PubMed:10553002, PubMed:18577768). May be involved in the oxidative metabolism of xenobiotics (Probable)
- Specific Function
- 4-nitrophenol 2-monooxygenase activity
- Gene Name
- CYP2E1
- Uniprot ID
- P05181
- Uniprot Name
- Cytochrome P450 2E1
- Molecular Weight
- 56848.42 Da
References
Drug created at September 22, 2015 21:09 / Updated at October 03, 2024 04:54