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Identification
NameDextropropoxyphene
Accession NumberDB00647  (APRD00548)
TypeSmall Molecule
GroupsApproved, Illicit, Withdrawn
Description

Dextropropoxyphene is an analgesic in the opioid category, patented (1955) and manufactured by Eli Lilly and Company. It is intended to treat mild pain and also has antitussive and local anaesthetic effects. The drug has been taken off the market in Europe and the US due to concerns of fatal overdoses and heart arrhythmias. An estimated 10 million patients have used these products.

The drug is often referred to as the general form, “propoxyphene”, however only the dextro-isomer (dextropropoxyphene) has any analgesic effect. The levo-isomer appears to exhibit a very limited antitussive effect.

Structure
Thumb
Synonyms
SynonymLanguageCode
d-PropoxypheneNot AvailableNot Available
DestropropossifeneNot AvailableNot Available
DextropropoxifenoSpanishINN
DextropropoxyphenGermanINN
DextropropoxyphèneFrenchINN
DextropropoxyphenumLatinINN
Salts
Name/CAS Structure Properties
Dextropropoxyphene Hydrochloride
1639-60-7
Thumb
  • InChI Key: QMQBBUPJKANITL-MYXGOWFTSA-N
  • Monoisotopic Mass: 375.196506916
  • Average Mass: 375.932
DBSALT000500
Dextropropoxyphene Napsylate
Thumb Not applicable DBSALT001000
Brand names
NameCompany
AbalginDLF
DacotonStandard
DarvonEli Lilly
Darvon-NPaladin
DeprancolParke Davis
DepronalPfizer
DoleneNot Available
DoloxeneAspen Pharmacare
PropoxypheneNot Available
Brand mixtures
Brand NameIngredients
Balacetacetaminophen + dextropropoxyphene
Capadexacetaminophen + dextropropoxyphene
Darvocetacetaminophen + dextropropoxyphene
Di-Antalvicacetaminophen + dextropropoxyphene
Lentogesicacetaminophen + dextropropoxyphene
Paradexacetaminophen + dextropropoxyphene
Propacetacetaminophen + dextropropoxyphene
Categories
CAS number469-62-5
WeightAverage: 339.4712
Monoisotopic: 339.219829177
Chemical FormulaC22H29NO2
InChI KeyXLMALTXPSGQGBX-PEODTPIXNA-N
InChI
InChI=1/C22H29NO2/c1-5-21(24)25-22(18(2)17-23(3)4,20-14-10-7-11-15-20)16-19-12-8-6-9-13-19/h6-15,18H,5,16-17H2,1-4H3/t18-,22+/s2
IUPAC Name
(2S,3R)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl propanoate
SMILES
CCC(=O)O[C@@](CC1=CC=CC=C1)([C@H](C)CN(C)C)C1=CC=CC=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassPhenylpropanoids and Polyketides
ClassStilbenes
SubclassNot Available
Direct parentStilbenes
Alternative parentsPhenylpropylamines; Benzyloxycarbonyls; Benzylethers; Tertiary Amines; Carboxylic Acid Esters; Dialkyl Ethers; Polyamines; Enolates
Substituentsbenzyloxycarbonyl; phenylpropylamine; benzylether; benzene; carboxylic acid ester; tertiary amine; enolate; carboxylic acid derivative; ether; dialkyl ether; polyamine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids.
Pharmacology
IndicationFor the relief of mild to moderate pain
PharmacodynamicsPropoxyphene, a synthetic opiate agonist, is structurally similar to methadone. Its general pharmacologic properties are those of the opiates as a group. The analgesic effect of propoxyphene is due to the d-isomer, dextropropoxyphene. It binds to the opiate receptors and leads to a decrease of the perception of pain stimuli. Propoxyphene possesses little to no antitussive activity and no antipyretic action.
Mechanism of actionPropoxyphene acts as a weak agonist at OP1, OP2, and OP3 opiate receptors within the central nervous system (CNS). Propoxyphene primarily affects OP3 receptors, which are coupled with G-protein receptors and function as modulators, both positive and negative, of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine, and noradrenaline is inhibited. Opioids such as propoxyphene also inhibit the release of vasopressin, somatostatin, insulin, and glucagon. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.
AbsorptionNot Available
Volume of distribution
  • 16 L/kg
Protein bindingNot Available
Metabolism

Hepatic

Route of eliminationThe major route of metabolism is cytochrome CYP3A4 mediated N-demethylation to norpropoxyphene, which is excreted by the kidneys. In 48 hours, approximately 20% to 25% of the administered dose of propoxyphene is excreted via the urine, most of which is free or conjugated norpropoxyphene.
Half life6-12 hours
Clearance
  • 2.6 L/min
ToxicityComa, respiratory depression, circulatory collapse, and pulmonary edema. Seizures occur more frequently in patients with propoxyphene intoxication than in those with opiate intoxication. LD50=230mg/kg (orally in rat, Emerson)
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Propoxyphene Action PathwayDrug actionSMP00672
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.997
Blood Brain Barrier + 0.9503
Caco-2 permeable + 0.7277
P-glycoprotein substrate Substrate 0.5798
P-glycoprotein inhibitor I Inhibitor 0.7851
P-glycoprotein inhibitor II Non-inhibitor 0.6469
Renal organic cation transporter Non-inhibitor 0.6086
CYP450 2C9 substrate Non-substrate 0.833
CYP450 2D6 substrate Non-substrate 0.9117
CYP450 3A4 substrate Substrate 0.6032
CYP450 1A2 substrate Inhibitor 0.6357
CYP450 2C9 substrate Non-inhibitor 0.7637
CYP450 2D6 substrate Inhibitor 0.6887
CYP450 2C19 substrate Non-inhibitor 0.7628
CYP450 3A4 substrate Non-inhibitor 0.7992
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.646
Ames test Non AMES toxic 0.8896
Carcinogenicity Carcinogens 0.7164
Biodegradation Not ready biodegradable 0.9714
Rat acute toxicity 2.9360 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9033
hERG inhibition (predictor II) Inhibitor 0.6837
Pharmacoeconomics
Manufacturers
  • Xanodyne pharmaceutics inc
  • Heritage pharmaceuticals inc
  • Mk laboratories inc
  • Halsey drug co inc
  • Alra laboratories inc
  • Impax laboratories inc
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Mutual pharmaceutical co inc
  • Mylan pharmaceuticals inc
  • Nexgen pharma inc
  • Par pharmaceutical inc
  • Purepac pharmaceutical co
  • Private formulations inc
  • Roxane laboratories inc
  • Sandoz inc
  • Teva pharmaceuticals usa inc
  • Valeant pharmaceuticals international
  • Vintage pharmaceuticals inc
  • Watson laboratories inc
  • West ward pharmaceutical corp
  • Whiteworth towne paulsen inc
  • Warner chilcott div warner lambert co
  • Aaipharma llc
Packagers
Dosage forms
FormRouteStrength
CapsuleOral
TabletOral
Prices
Unit descriptionCostUnit
Propoxyphene napsylate powder5.33USDg
Darvon-n 100 mg tablet2.16USDtablet
Darvon 65 mg capsule1.71USDcapsule
Propoxyphene N-APAP 100-500 mg tablet1.6USDtablet
Darvon 65 mg pulvule1.49USDeach
Propoxyphene N-APAP 50-325 mg tablet1.32USDtablet
Propoxyphene-APAP 65-650 mg tablet0.57USDtablet
Propoxyphene N-APAP 100-650 mg tablet0.47USDtablet
Propoxyphene hcl 65 mg capsule0.43USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point75.5 °CPhysProp
water solubility3.32 mg/L (at 25 °C)MCFARLAND,JW ET AL. (2001)
logP4.18HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.00419ALOGPS
logP4.06ALOGPS
logP4.9ChemAxon
logS-4.9ALOGPS
pKa (Strongest Basic)9.52ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area29.54 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity102.88 m3·mol-1ChemAxon
Polarizability38.86 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Carl R. White, “Synthesis and purification of d-propoxyphene hydrochloride.” U.S. Patent US4661625, issued April, 1973.

US4661625
General Reference
  1. Coda BA, Rudy AC, Archer SM, Wermeling DP: Pharmacokinetics and bioavailability of single-dose intranasal hydromorphone hydrochloride in healthy volunteers. Anesth Analg. 2003 Jul;97(1):117-23, table of contents. Pubmed
External Links
ResourceLink
KEGG DrugD07809
KEGG CompoundC07406
ChEBI51173
ChEMBL
Therapeutic Targets DatabaseDAP000017
PharmGKBPA451142
RxListhttp://www.rxlist.com/cgi/generic/propox.htm
Drugs.comhttp://www.drugs.com/propoxyphene.html
WikipediaPropoxyphene
ATC CodesN02AC04N02AC54N02AC74
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(46.1 KB)
Interactions
Drug Interactions
Drug
AcenocoumarolPropoxyphene may increase the anticoagulant effect of acenocoumarol.
AlvimopanIncreases levels by receptor binding competition. Discontinue opioid administration at least 7 days prior to administrating Alvimopan.
AnisindionePropoxyphene may increase the anticoagulant effect of anisindione.
AtomoxetineThe CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine
CarbamazepinePropoxyphene increases the effect of carbamazepine
CimetidineCimetidine, a moderate CYP3A4 inhibitor, may decrease the metabolism of propoxyphene. Monitor for changes in the therapeutic and adverse effects of propoxyphene if cimetidine is intitiated, discontinued or dose changed.
DicoumarolPropoxyphene may increase the anticoagulant effect of dicumarol.
Insulin LisproConcomitant therapy with drugs that may increase the blood-glucose-lowering effect of insulin lispro and thus the chance of hypoglycemia should be monitored closely.
RitonavirRitonavir increases the levels of analgesic
TranylcypromineIncreased risk of serotonin syndrome. Concomitant use should be avoided.
TriprolidineThe CNS depressants, Triprolidine and Propoxyphene, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
WarfarinPropoxyphene may increase the anticoagulant effect of warfarin.
Food Interactions
  • Take without regard to meals. Avoid alcohol.

Targets

1. Mu-type opioid receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Mu-type opioid receptor P35372 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Ulens C, Daenens P, Tytgat J: Norpropoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents. Cardiovasc Res. 1999 Dec;44(3):568-78. Pubmed
  3. Tyers MB: A classification of opiate receptors that mediate antinociception in animals. Br J Pharmacol. 1980 Jul;69(3):503-12. Pubmed
  4. Picker MJ: Discriminative stimulus effects of the mixed-opioid agonist/antagonist dezocine: cross-substitution by mu and delta opioid agonists. J Pharmacol Exp Ther. 1997 Dec;283(3):1009-17. Pubmed
  5. Codd EE, Shank RP, Schupsky JJ, Raffa RB: Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther. 1995 Sep;274(3):1263-70. Pubmed
  6. Bannwarth B, Richez C: The dextropropoxyphene controversy. Joint Bone Spine. 2009 Oct;76(5):449-51. Epub 2009 Jul 14. Pubmed
  7. Walker EA, Tiano MJ, Benyas SI, Dykstra LA, Picker MJ: Naltrexone and beta-funaltrexamine antagonism of the antinociceptive and response rate-decreasing effects of morphine, dezocine, and d-propoxyphene. Psychopharmacology (Berl). 1999 May;144(1):45-53. Pubmed

2. Delta-type opioid receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Delta-type opioid receptor P41143 Details

References:

  1. Neil A: Affinities of some common opioid analgesics towards four binding sites in mouse brain. Naunyn Schmiedebergs Arch Pharmacol. 1984 Nov;328(1):24-9. Pubmed

3. Kappa-type opioid receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Kappa-type opioid receptor P41145 Details

References:

  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Neil A: Affinities of some common opioid analgesics towards four binding sites in mouse brain. Naunyn Schmiedebergs Arch Pharmacol. 1984 Nov;328(1):24-9. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

4. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

5. Cytochrome P450 3A7

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 3A7 P24462 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on January 16, 2014 11:03