Identification

Name
Loxoprofen
Accession Number
DB09212
Description

Loxoprofen is a propionic acid derivative non-steroidal anti-inflammatory drug. It is marketed under the trade name Loxonin in Brazil, Mexico and Japan by Sankyo, as Loxomac in India, and as Oxeno in Argentina. A transdermal preparation was approved for use in Japan in January 2006.

Type
Small Molecule
Groups
Approved
Structure
Thumb
Weight
Average: 246.3016
Monoisotopic: 246.125594442
Chemical Formula
C15H18O3
Synonyms
  • Loxoprofen
  • Loxoprofene
  • Loxoprofeno
  • Loxoprofenum

Pharmacology

Indication

Loxoprofen is non-steroidal anti-inflammatory medication (NSAID) indicated for pain and inflammation related to musculoskeletal and joint disorders.6 In addition to its effects on pain, it is an antipyretic and anti-inflammatory medication.7

Contraindications & Blackbox Warnings
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Pharmacodynamics

Loxoprofen is a non-selective inhibitor of cyclooxygenase enzymes, which are responsible for the formation of various biologically active pain, fever, and inflammatory mediators. These include prostaglandins, prostacyclin, thromboxane, and arachidonic acid.7,8

Mechanism of action

Loxoprofen itself is a prodrug and carries little-to-no pharmacological activity - it is rapidly metabolized to its trans-alcohol form, which is a potent and non-selective inhibitor of cyclooxygenase.3 Cyclooxygenase (COX) is present in 2 forms, COX-1 and COX-2, with each serving different functions. COX-1 is present in human cells and is constitutively released, performing cellular housekeeping functions such as mucus production and platelet aggregation.8 COX-2 is induced in human cells post-injury or due to other stimuli, is triggered to appear in large quantities at the sites of injury/stimuli, and is ultimately responsible for the mediation of inflammation and pain.8

Loxoprofen's active metabolite inhibits both COX isoforms, resulting in reduced expression of several mediators of pain, inflammation, and fever (e.g. prostaglandins, prostacyclin, thromboxane, etc).8

TargetActionsOrganism
AProstaglandin G/H synthase 2
antagonist
Humans
AProstaglandin G/H synthase 1
antagonist
Humans
Absorption

Loxoprofen is rapidly and completely absorbed from the GI tract with a bioavailability of 95%.14 The absorption phase of the medication occurs in the first 4-6 hours after ingestion. Food ingestion with the medication causes a slight decrease in the rate of loxoprofen absorption.14

Volume of distribution

Loxoprofen has a volume of distribution of 0.16 L/kg.14

Protein binding

99% albumin-bound.14 At doses of loxoprofen greater than 500 mg/day, clearance of the drug increases as saturation of plasma protein binding occurs at higher doses.14

Metabolism

Loxoprofen is a prodrug that is rapidly converted to its active trans-alcohol metabolite by carbonyl reductase in the liver.2 This same process also results in a cis-alcohol metabolite, though this isomer carries little pharmacological activity.1,3 The parent drug has also been observed to undergo oxidation via CYP3A4/5 to two hydroxylated metabolites (M3 and M4) and glucuronidation by UGT2B7 to two glucuronide metabolites (M5 and M6).1 The alcohol metabolites of loxoprofen also undergo glucuronide conjugation via UGT2B7 to two glucuronide metabolites (M7 and M8) prior to excretion.1

When applied in topical formulations, loxoprofen is metabolized to its active trans-alcohol form by carbonyl reductase in the skin.4

Hover over products below to view reaction partners

Route of elimination

50% renal excretion.13 This drug is 20% - 30% excreted in the stool.10,13

Half-life

The elimination half-life of Loxoprofen is approximately 15 hours.14 Steady concentration is achieved after 2-3 doses.14

Clearance

Most of the drug as unchanged loxoprofen, 6-0-desmethyl loxoprofen (less than 1%) and glucuronide or other conjugates (66-92%).13

In patients with renal failure, metabolites may accumulate.14

Adverse Effects
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Toxicity

Adverse effects include anorexia, nausea, vomiting, bleeding, anemia, diarrhea, and constipation.13 Loxoprofen toxicity may lead to gastrointestinal disturbance (including flatulence, dyspepsia and gastritis) and renal failure.14

Affected organisms
Not Available
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
AbacavirLoxoprofen may decrease the excretion rate of Abacavir which could result in a higher serum level.
AbciximabThe risk or severity of bleeding and hemorrhage can be increased when Loxoprofen is combined with Abciximab.
AcarboseLoxoprofen may decrease the excretion rate of Acarbose which could result in a higher serum level.
AcebutololLoxoprofen may decrease the antihypertensive activities of Acebutolol.
AceclofenacThe risk or severity of adverse effects can be increased when Aceclofenac is combined with Loxoprofen.
AcemetacinThe risk or severity of adverse effects can be increased when Loxoprofen is combined with Acemetacin.
AcenocoumarolThe risk or severity of bleeding and hemorrhage can be increased when Loxoprofen is combined with Acenocoumarol.
AcetaminophenThe risk or severity of adverse effects can be increased when Loxoprofen is combined with Acetaminophen.
AcetohexamideThe protein binding of Acetohexamide can be decreased when combined with Loxoprofen.
Acetylsalicylic acidThe risk or severity of adverse effects can be increased when Acetylsalicylic acid is combined with Loxoprofen.
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

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
Not Available

Products

Product Ingredients
IngredientUNIICASInChI Key
Loxoprofen sodiumNDC2M7399S80382-23-6WORCCYVLMMTGFR-UHFFFAOYSA-M
International/Other Brands
Loxomac / Loxonin / Oxeno

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as phenylpropanoic acids. These are compounds with a structure containing a benzene ring conjugated to a propanoic acid.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Phenylpropanoic acids
Sub Class
Not Available
Direct Parent
Phenylpropanoic acids
Alternative Parents
Monocyclic monoterpenoids / Aromatic monoterpenoids / Benzene and substituted derivatives / Cyclic ketones / Monocarboxylic acids and derivatives / Carboxylic acids / Organic oxides / Hydrocarbon derivatives
Substituents
2-phenylpropanoic-acid / Aromatic homomonocyclic compound / Aromatic monoterpenoid / Benzenoid / Carbonyl group / Carboxylic acid / Carboxylic acid derivative / Cyclic ketone / Hydrocarbon derivative / Ketone
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
monocarboxylic acid, cyclopentanones (CHEBI:76172)

Chemical Identifiers

UNII
3583H0GZAP
CAS number
68767-14-6
InChI Key
YMBXTVYHTMGZDW-UHFFFAOYSA-N
InChI
InChI=1S/C15H18O3/c1-10(15(17)18)12-7-5-11(6-8-12)9-13-3-2-4-14(13)16/h5-8,10,13H,2-4,9H2,1H3,(H,17,18)
IUPAC Name
2-{4-[(2-oxocyclopentyl)methyl]phenyl}propanoic acid
SMILES
CC(C(O)=O)C1=CC=C(CC2CCCC2=O)C=C1

References

General References
  1. Shrestha R, Cho PJ, Paudel S, Shrestha A, Kang MJ, Jeong TC, Lee ES, Lee S: Exploring the Metabolism of Loxoprofen in Liver Microsomes: The Role of Cytochrome P450 and UDP-Glucuronosyltransferase in Its Biotransformation. Pharmaceutics. 2018 Aug 2;10(3). pii: pharmaceutics10030112. doi: 10.3390/pharmaceutics10030112. [PubMed:30072626]
  2. Quinones-Lombrana A, Li N, Del Solar V, Atilla-Gokcumen GE, Blanco JG: CBR1 rs9024 genotype status impacts the bioactivation of loxoprofen in human liver. Biopharm Drug Dispos. 2018 Jun;39(6):315-318. doi: 10.1002/bdd.2135. [PubMed:29851133]
  3. Riendeau D, Salem M, Styhler A, Ouellet M, Mancini JA, Li CS: Evaluation of loxoprofen and its alcohol metabolites for potency and selectivity of inhibition of cyclooxygenase-2. Bioorg Med Chem Lett. 2004 Mar 8;14(5):1201-3. [PubMed:14980665]
  4. Sawamura R, Sakurai H, Wada N, Nishiya Y, Honda T, Kazui M, Kurihara A, Shinagawa A, Izumi T: Bioactivation of loxoprofen to a pharmacologically active metabolite and its disposition kinetics in human skin. Biopharm Drug Dispos. 2015 Sep;36(6):352-363. doi: 10.1002/bdd.1945. Epub 2015 Apr 21. [PubMed:25765700]
  5. Loxoprofen [Link]
  6. MIMS LOXOPROFEN [Link]
  7. Mechanism of action of non steroidal anti-inflammatory drugs [Link]
  8. Non-Steroidal Anti-Inflammatory Drugs: An Overview of Cardiovascular Risks [Link]
  9. Loxoprofen Sodium, a Non-Selective NSAID, Reduces Atherosclerosis in Mice by Reducing Inflammation [Link]
  10. Comparison of Pharmacokinetics between Loxoprofen and Its Derivative with Lower Ulcerogenic Activity, Fluoro-loxoprofen [Link]
  11. Comparison of Pharmacokinetics between Loxoprofen and Its Derivative with Lower Ulcerogenic Activity, Fluoro-loxoprofen [Link]
  12. Aspirin, Non-Aspirin Nonsteroidal Anti-inflammatory Drugs, or Acetaminophen and risk of ovarian cancer [Link]
  13. LOXOPROFEN [Link]
  14. Loxoprofen Sodium [Link]
  15. Roxonin [Link]
Human Metabolome Database
HMDB0041920
KEGG Drug
D08149
PubChem Compound
3965
PubChem Substance
310265119
ChemSpider
3828
BindingDB
50140320
RxNav
28908
ChEBI
76172
ChEMBL
CHEMBL19299
PharmGKB
PA166049180
Wikipedia
Loxoprofen

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentAnkylosing Spondylitis (AS)1
4CompletedTreatmentHealthy Volunteers1
3CompletedTreatmentAcute Upper Respiratory Infection / Fever1
3CompletedTreatmentBack Pain Lower Back1
3CompletedTreatmentPain1
3CompletedTreatmentPain / Traumas1
3CompletedTreatmentProlapsed Lumbar Disc1
2CompletedTreatmentChronic Non-specific, Uncomplicated Neck Pain1
2CompletedTreatmentDelayed Onset Muscle Soreness1
2CompletedTreatmentRheumatoid Arthritis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
GelTopical1 %
TabletOral60 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)108.5 - 111Not Available
boiling point (°C)220.7Not Available
water solubility47 mg/mLNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0663 mg/mLALOGPS
logP2.99ALOGPS
logP3.35ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)4.19ChemAxon
pKa (Strongest Basic)-7.4ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area54.37 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity68.8 m3·mol-1ChemAxon
Polarizability27.08 Å3ChemAxon
Number of Rings2ChemAxon
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

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
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. Riendeau D, Salem M, Styhler A, Ouellet M, Mancini JA, Li CS: Evaluation of loxoprofen and its alcohol metabolites for potency and selectivity of inhibition of cyclooxygenase-2. Bioorg Med Chem Lett. 2004 Mar 8;14(5):1201-3. [PubMed:14980665]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
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. Riendeau D, Salem M, Styhler A, Ouellet M, Mancini JA, Li CS: Evaluation of loxoprofen and its alcohol metabolites for potency and selectivity of inhibition of cyclooxygenase-2. Bioorg Med Chem Lett. 2004 Mar 8;14(5):1201-3. [PubMed:14980665]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
General Function
Prostaglandin-e2 9-reductase activity
Specific Function
NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. ...
Gene Name
CBR1
Uniprot ID
P16152
Uniprot Name
Carbonyl reductase [NADPH] 1
Molecular Weight
30374.73 Da
References
  1. Shrestha R, Cho PJ, Paudel S, Shrestha A, Kang MJ, Jeong TC, Lee ES, Lee S: Exploring the Metabolism of Loxoprofen in Liver Microsomes: The Role of Cytochrome P450 and UDP-Glucuronosyltransferase in Its Biotransformation. Pharmaceutics. 2018 Aug 2;10(3). pii: pharmaceutics10030112. doi: 10.3390/pharmaceutics10030112. [PubMed:30072626]
  2. Quinones-Lombrana A, Li N, Del Solar V, Atilla-Gokcumen GE, Blanco JG: CBR1 rs9024 genotype status impacts the bioactivation of loxoprofen in human liver. Biopharm Drug Dispos. 2018 Jun;39(6):315-318. doi: 10.1002/bdd.2135. [PubMed:29851133]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...

Components:
References
  1. Shrestha R, Cho PJ, Paudel S, Shrestha A, Kang MJ, Jeong TC, Lee ES, Lee S: Exploring the Metabolism of Loxoprofen in Liver Microsomes: The Role of Cytochrome P450 and UDP-Glucuronosyltransferase in Its Biotransformation. Pharmaceutics. 2018 Aug 2;10(3). pii: pharmaceutics10030112. doi: 10.3390/pharmaceutics10030112. [PubMed:30072626]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Glucuronosyltransferase activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds.Its unique specificity for 3,4-catechol estrogens and estriol su...
Gene Name
UGT2B7
Uniprot ID
P16662
Uniprot Name
UDP-glucuronosyltransferase 2B7
Molecular Weight
60694.12 Da
References
  1. Shrestha R, Cho PJ, Paudel S, Shrestha A, Kang MJ, Jeong TC, Lee ES, Lee S: Exploring the Metabolism of Loxoprofen in Liver Microsomes: The Role of Cytochrome P450 and UDP-Glucuronosyltransferase in Its Biotransformation. Pharmaceutics. 2018 Aug 2;10(3). pii: pharmaceutics10030112. doi: 10.3390/pharmaceutics10030112. [PubMed:30072626]

Drug created on October 20, 2015 15:51 / Updated on June 12, 2020 10:52

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