Identification

Name
Lofexidine
Accession Number
DB04948
Type
Small Molecule
Groups
Approved, Investigational
Description

Lofexidine is a non-opioid centrally acting alpha2-adrenergic receptor agonist that was first approved for the treatment of opioid withdrawal in the United Kingdom in 1992.[2] It was first studied for use as an antihypertensive in 1980, but its researched was stopped as it was found less effective for the treatment of hypertension than clonidine.[6] Lofexidine was then repurposed for the treatment of opioid withdrawal, as it was seen to be more economical and have fewer side effects than clonidine.[5] Lofexidine was developed by US Woldmeds LLC and it was approved by the FDA on May 16, 2018.[8]

Structure
Thumb
Synonyms
  • 2-(alpha-(2,6-Dichlorophenoxy)ethyl)2-imidazoline
  • Lofexidina
  • Lofexidinum
Product Ingredients
IngredientUNIICASInChI Key
Lofexidine hydrochlorideV47G1SDI1B21498-08-8DWWHMKBNNNZGHF-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
LucemyraTablet, film coated0.2 mg/1OralUs World Meds, Llc2018-06-18Not applicableUs
International/Other Brands
Britlofex (Britannia)
Categories
UNII
UI82K0T627
CAS number
31036-80-3
Weight
Average: 259.132
Monoisotopic: 258.03266843
Chemical Formula
C11H12Cl2N2O
InChI Key
KSMAGQUYOIHWFS-UHFFFAOYSA-N
InChI
InChI=1S/C11H12Cl2N2O/c1-7(11-14-5-6-15-11)16-10-8(12)3-2-4-9(10)13/h2-4,7H,5-6H2,1H3,(H,14,15)
IUPAC Name
2-[1-(2,6-dichlorophenoxy)ethyl]-4,5-dihydro-1H-imidazole
SMILES
CC(OC1=C(Cl)C=CC=C1Cl)C1=NCCN1

Pharmacology

Indication

Lofexidine is indicated for mitigation of symptoms associated with acute withdrawal from opioids and for facilitation of the completion of opioid discontinuation treatment. It is the first non-opioid medication for the symptomatic management of opioid discontinuation.[9]

Opioid withdrawal syndrome is a debilitating manifestation of opioid dependence.[3] This condition is extremely unpleasant lasting several days with some of the main features being abdominal pain, nausea, diarrhea, mydriasis, lacrimation, and piloerection. These symptoms are often observed after abrupt reductions in the opioid dose and can be resolved by re-administration of the opioid.[4]

Associated Conditions
Pharmacodynamics

In clinical trials, lofexidine presented more severe opioid withdrawal effects than observed with methadone. On the other hand, in clinical trials of methadone withdrawal, lofexidine effectively reduced withdrawal symptoms, especially hypotension.[5] The clinical reports have also indicated that lofexidine presents a better outcome when used briefly.[6] In phase 3 clinical trials, lofexidine was shown to generate a significantly higher completion rate of opioid discontinuation. Some pharmacological studies were performed and there were no off-target effects reported.[9]

Mechanism of action

Lofexidine is a potent alpha2-adrenergic receptor agonist with some moderate agonistic affinity towards Alpha-1A adrenergic receptor and 5-HT1a, 5-HT7, 5HT2c and 5HT1d receptors.[9]

The alpha2-adrenergic receptor is normally targeted by norepinephrine and its activation inhibits the synthesis of cAMP which in turn leads to potassium efflux and suppression of neural firing and inhibition of norepinephrine release. All of this activity can reduce the heart rate, blood pressure, and attenuate sympathetic stress response.[9]

Opioids inhibit cAMP in the noradrenergic neurons and their discontinuation produces a rise in the level of cAMP. This will generate an increase in norepinephrine which is associated with the symptoms of withdrawal. The magnitude of the effect is augmented by chronic opioid use due to the compensatory mechanisms of continuous negative feedback. Therefore, chronic opioid use translates into an exacerbated production of cAMP and norepinephrine release.[9]

Lofexidine replaces the opioid-driven inhibition of cAMP production by activating the alpha2-adrenergic receptor and moderating the symptoms of opioid withdrawal. This effect is performed without interacting with opioid receptors which mediate other activities of opioid dependence or addiction.[9]

TargetActionsOrganism
AAlpha-2A adrenergic receptor
agonist
Human
NAlpha-1A adrenergic receptor
agonist
Human
N5-hydroxytryptamine receptor 1A
agonist
Human
N5-hydroxytryptamine receptor 7
agonist
Human
N5-hydroxytryptamine receptor 2C
agonist
Human
N5-hydroxytryptamine receptor 1D
agonist
Human
Absorption

Lofexidine has a good oral bioavailability and the peak plasma concentration occurs after 2-5 hours of oral administration.[6] The bioavailability is registered to be even higher than 72%.[7] About 30% of the administered dose of lofexidine is lost during first-pass metabolism. The absorption is registered to be very rapidly recirculated in the gut. After oral administration of 0.8 mg of lofexidine, a maximal dose of 1.26 ng/ml is achieved after 3 hours.[9]

Volume of distribution

Lofexidine has a volume of distribution of 300 L, indicating that it distributes readily into the tissues.[9]

Protein binding

The protein binding of lofexidine is determined to be moderate and it represents about 55% of the administered dose.[9]

Metabolism

Lofexidine metabolic ratio is highly variable among people.[6] It is metabolized mainly by the activity of CYP2D6 and in a minor degree by CYP1A2 and CYP2C19. These enzymes catalyze the hydroxylation of lofexidine and the opening of imidazoline ring to form N-(2-aminoethyl)-2-(2,6-dichlorophenoxy)propanamide. This metabolite is deamidated and forms 2-(2,6-dichlorophenoxy) propionic acid and 2,6-dichlorophenol. These three main metabolites are inactive.[9]

Route of elimination

The elimination of lofexidine is primarily through the renal system and it represents 94% of the administered dose while elimination in feces corresponds to only 0.93%.[6] From the eliminated dose in urine, about 10% is formed by unchanged drug and 5% is constituted by the first hydrolysis product N-(2-aminoethyl)-2-(2,6-dichlorophenoxy)propanamide. 2,6-dichlorophenol represents the majority of the administered dose by occupying about 80% of the administered dose.[9]

Half life

The reported elimination half-life of lofexidine is 11 hours.[7]

Clearance

The total elimination clearance following intravenous administration is 17.6 L/h.[9]

Toxicity

Lofexidine did not exhibit genotoxic, mutagenic nor mutagenic potential. Administration at gestational period showed a reduction in the neonatal weight, survival, and increased abortion.[9]

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

Interactions

Drug Interactions
DrugInteraction
7-NitroindazoleThe therapeutic efficacy of 7-Nitroindazole can be increased when used in combination with Lofexidine.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe metabolism of Lofexidine can be decreased when combined with 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline.
AbirateroneThe serum concentration of Lofexidine can be increased when it is combined with Abiraterone.
AcebutololThe therapeutic efficacy of Lofexidine can be decreased when used in combination with Acebutolol.
AcemetacinThe therapeutic efficacy of Lofexidine can be decreased when used in combination with Acemetacin.
AcepromazineThe therapeutic efficacy of Acepromazine can be increased when used in combination with Lofexidine.
AceprometazineThe therapeutic efficacy of Aceprometazine can be increased when used in combination with Lofexidine.
AcetaminophenAcetaminophen may decrease the excretion rate of Lofexidine which could result in a higher serum level.
Acetylsalicylic acidThe therapeutic efficacy of Lofexidine can be decreased when used in combination with Acetylsalicylic acid.
AdipiplonThe therapeutic efficacy of Adipiplon can be increased when used in combination with Lofexidine.
Food Interactions
Not Available

References

Synthesis Reference

U.S. Patent 3,966,757.

General References
  1. Walsh SL, Strain EC, Bigelow GE: Evaluation of the effects of lofexidine and clonidine on naloxone-precipitated withdrawal in opioid-dependent humans. Addiction. 2003 Apr;98(4):427-39. [PubMed:12653813]
  2. Haney M, Hart CL, Vosburg SK, Comer SD, Reed SC, Foltin RW: Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse. Psychopharmacology (Berl). 2008 Mar;197(1):157-68. doi: 10.1007/s00213-007-1020-8. Epub 2007 Dec 27. [PubMed:18161012]
  3. Rehni AK, Jaggi AS, Singh N: Opioid withdrawal syndrome: emerging concepts and novel therapeutic targets. CNS Neurol Disord Drug Targets. 2013 Feb 1;12(1):112-25. [PubMed:23244430]
  4. Juurlink DN, Dhalla IA: Dependence and addiction during chronic opioid therapy. J Med Toxicol. 2012 Dec;8(4):393-9. doi: 10.1007/s13181-012-0269-4. [PubMed:23073725]
  5. Ries R. and Miller S. (2009). Principles of Addiction Medicine (4th ed.). Lippincott Williams & Wilkins. [ISBN:978-0-7817-7477-2]
  6. Strain E. and Stitzer M. (2006). The treatment of Opiod Dependence. The Johns Hopkins University Press. [ISBN:0-8018-8303-2]
  7. Zaragoza Dorwald F. (2012). Lead optimization for medicinal chemists. Wiley-VCH.
  8. FDA News [Link]
  9. FDA reports [Link]
External Links
Human Metabolome Database
HMDB0015606
PubChem Compound
30668
PubChem Substance
46508453
ChemSpider
28460
BindingDB
50019646
ChEBI
51368
ChEMBL
CHEMBL17860
Therapeutic Targets Database
DAP000064
PharmGKB
PA164744510
Wikipedia
Lofexidine
ATC Codes
N07BC04 — Lofexidine
FDA label
Download (530 KB)
MSDS
Download (72.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHealthy Volunteers1
1CompletedBasic ScienceNormal Healthy Volunteers1
1CompletedBasic ScienceNormal Healthy Volunteers Will be Treated With Lofexidine to Understand the Absolute Bioavailability and Mass Balance Recovery of the Product / Normal Healthy Volunteers Will be Treated With Lofexidine to Understand the Absolute Bioavailbility and Mass Balance Recovery of the Product1
1CompletedBasic ScienceRenally Impaired Subjects1
1CompletedTreatmentBuprenorphine Withdrawal Syndrome / Opioid Dependence1
1CompletedTreatmentHealthy Volunteers2
1CompletedTreatmentHepatic Failure1
1CompletedTreatmentHeroin Dependence1
1CompletedTreatmentMethadone Withdrawal Syndrome / Opioid Dependence2
1CompletedTreatmentOpioid-Related Disorders1
1CompletedTreatmentOpioid-Related Disorders / Substance-Related Disorders2
1TerminatedTreatmentCocaine Related Disorders1
2CompletedBasic ScienceMarijuana Dependence1
2CompletedTreatmentOpioid-Related Disorders1
2, 3CompletedTreatmentCannabis Dependence / Marijuana Dependence1
3CompletedTreatmentAcute Opioid Withdrawal Syndrome / Opioid Dependence1
3CompletedTreatmentOpiate Addiction1
3CompletedTreatmentOpiate withdrawal symptoms1
3CompletedTreatmentOpioid-Related Disorders1
4CompletedTreatmentOpiate Dependent Patients Who Are Undergoing Inpatient Detoxification in Singapore1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral0.2 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)221-223U.S. Patent 3,966,757.
boiling point (°C)421.5 ºC at 760 mm Hg'MSDS'
water solubilitySoluble'MSDS'
logP5.37FDA Advisory Committee Briefing Document.
pKa9.43FDA Advisory Committee Briefing Document.
Predicted Properties
PropertyValueSource
Water Solubility0.147 mg/mLALOGPS
logP3.31ALOGPS
logP2.66ChemAxon
logS-3.2ALOGPS
pKa (Strongest Basic)7.67ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area33.62 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity64.41 m3·mol-1ChemAxon
Polarizability25.11 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9969
Blood Brain Barrier+0.9582
Caco-2 permeable+0.539
P-glycoprotein substrateSubstrate0.7119
P-glycoprotein inhibitor INon-inhibitor0.9326
P-glycoprotein inhibitor IINon-inhibitor0.8089
Renal organic cation transporterInhibitor0.6897
CYP450 2C9 substrateNon-substrate0.744
CYP450 2D6 substrateNon-substrate0.6421
CYP450 3A4 substrateNon-substrate0.5055
CYP450 1A2 substrateInhibitor0.8023
CYP450 2C9 inhibitorNon-inhibitor0.739
CYP450 2D6 inhibitorInhibitor0.6616
CYP450 2C19 inhibitorNon-inhibitor0.6593
CYP450 3A4 inhibitorNon-inhibitor0.9304
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5075
Ames testNon AMES toxic0.7322
CarcinogenicityNon-carcinogens0.913
BiodegradationNot ready biodegradable0.996
Rat acute toxicity2.9567 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6244
hERG inhibition (predictor II)Non-inhibitor0.7293
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0bta-5090000000-966c69c881b261c7d39d

Taxonomy

Description
This compound belongs to the class of organic compounds known as dichlorobenzenes. These are compounds containing a benzene with exactly two chlorine atoms attached to it.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Halobenzenes
Direct Parent
Dichlorobenzenes
Alternative Parents
Phenoxy compounds / Phenol ethers / Alkyl aryl ethers / Imidolactams / Aryl chlorides / Imidazolines / Propargyl-type 1,3-dipolar organic compounds / Carboximidamides / Carboxamidines / Azacyclic compounds
show 3 more
Substituents
Phenoxy compound / 1,3-dichlorobenzene / Phenol ether / Alkyl aryl ether / Aryl chloride / Aryl halide / Imidolactam / 2-imidazoline / Amidine / Carboxylic acid amidine
show 15 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
aromatic ether, imidazoles, carboxamidine, dichlorobenzene (CHEBI:51368)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Thioesterase binding
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazo...
Gene Name
ADRA2A
Uniprot ID
P08913
Uniprot Name
Alpha-2A adrenergic receptor
Molecular Weight
48956.275 Da
References
  1. Jin Y, Verstappen A, Elko E, Cammarata P, Yorio T: Effects of lofexidine, an alpha 2-adrenoreceptor agonist, on ocular blood flow and ion transport of rabbit iris-ciliary body. J Ocul Pharmacol. 1992 Spring;8(1):23-33. [PubMed:1357064]
  2. Strang J, Bearn J, Gossop M: Lofexidine for opiate detoxification: review of recent randomised and open controlled trials. Am J Addict. 1999 Fall;8(4):337-48. [PubMed:10598217]
  3. Erb S, Hitchcott PK, Rajabi H, Mueller D, Shaham Y, Stewart J: Alpha-2 adrenergic receptor agonists block stress-induced reinstatement of cocaine seeking. Neuropsychopharmacology. 2000 Aug;23(2):138-50. [PubMed:10882840]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Agonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...
Gene Name
ADRA1A
Uniprot ID
P35348
Uniprot Name
Alpha-1A adrenergic receptor
Molecular Weight
51486.005 Da
References
  1. FDA reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Agonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances. Ligand binding causes a conformation change that triggers...
Gene Name
HTR1A
Uniprot ID
P08908
Uniprot Name
5-hydroxytryptamine receptor 1A
Molecular Weight
46106.335 Da
References
  1. FDA reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Agonist
General Function
Serotonin receptor activity
Specific Function
This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor ...
Gene Name
HTR7
Uniprot ID
P34969
Uniprot Name
5-hydroxytryptamine receptor 7
Molecular Weight
53554.43 Da
References
  1. FDA reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Agonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1-2,5,-dimethoxy-4-...
Gene Name
HTR2C
Uniprot ID
P28335
Uniprot Name
5-hydroxytryptamine receptor 2C
Molecular Weight
51820.705 Da
References
  1. FDA reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Agonist
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for ergot alkaloid derivatives, various anxiolytic and antidepressant drugs and other psychoactive subst...
Gene Name
HTR1D
Uniprot ID
P28221
Uniprot Name
5-hydroxytryptamine receptor 1D
Molecular Weight
41906.38 Da
References
  1. FDA reports [Link]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. FDA reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
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 oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. FDA reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
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 im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. FDA reports [Link]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Efflux transmembrane transporter activity
Specific Function
Drug efflux transporter present in a number of stem cells that acts as a regulator of cellular differentiation. Able to mediate efflux from cells of the rhodamine dye and of the therapeutic drug do...
Gene Name
ABCB5
Uniprot ID
Q2M3G0
Uniprot Name
ATP-binding cassette sub-family B member 5
Molecular Weight
138639.48 Da
References
  1. FDA reports [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Monovalent cation:proton antiporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
References
  1. FDA reports [Link]

Drug created on October 21, 2007 16:23 / Updated on August 02, 2018 07:44