Identification

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Name
Methadone
Accession Number
DB00333  (APRD00485)
Type
Small Molecule
Groups
Approved
Description

Methadone is a potent synthetic analgesic that works as a full µ-opioid receptor (MOR) agonist and N-methyl-d-aspartate (NMDA) receptor antagonist. As a full MOR agonist, methadone mimics the natural effects of the body's opioids, endorphins, and enkephalins through the release of neurotransmitters involved in pain transmission. It also has a number of unique characteristics that have led to its increased use in the last two decades; in particular, methadone has a lower risk of neuropsychiatric toxicity compared to other opioids (due to a lack of active metabolites), minimal accumulation in renal failure, good bioavailability, low cost, and a long duration of action.21,22,23,14,19,20

Due to its unique mechanism of action, methadone is particularly useful for the management of hard to treat pain syndromes such as neuropathic pain and cancer pain requiring higher and more frequent doses of shorter-acting opioids.15,16,18 Compared with morphine, the gold standard reference opioid, methadone also acts as an agonist of κ- and σ-opioid receptors, as an antagonist of the N-methyl-D-aspartate (NMDA) receptor, and as an inhibitor of serotonin and norepinephrine uptake.2,7 Specifically by inhibiting the NMDA receptor, methadone dampens a major excitatory pain pathway within the central nervous system.12 Compared to other opioids, methadone's effects on NMDA inhibition may explain it's improved analgesic efficacy and reduced opioid tolerance.16,17

Methadone shares similar effects and risks of other opioids such as morphine, hydromorphone, oxycodone, and fentanyl. However, it also has a unique pharmacokinetic profile. Compared with short-acting and even extended-release formulations of morphine, methadone displays a comparatively longer duration of action and half-life. These effects make methadone a good option for the treatment of severe pain and addiction as fewer doses are needed to maintain analgesia and prevent opioid withdrawal symptoms. However, methadone also has an unpredictable half-life with interindividual variability, which leads to an unpredictable risk of respiratory depression and overdose when initiating or titrating therapy.8

Overall, methadone's pharmacological actions result in analgesia, suppression of opioid withdrawal symptoms, sedation, miosis, sweating, hypotension, bradycardia, nausea and vomiting (via binding within the chemoreceptor trigger zone), and constipation. At higher doses, methadone use can result in respiratory depression, overdose, and death.21,22,23

Treatment of opioid addiction with methadone, buprenorphine, or slow-release oral morphine (SROM) is termed Opioid Agonist Treatment (OAT) or Opioid Substitution Therapy (OST). The intention of substitution of illicit opioids with the long-acting opioids used in OAT is to prevent withdrawal symptoms for 24-36 hours following dosing to ultimately reduce cravings and drug-seeking behaviours. Use of OAT is also intended to lead to social stabilization by reducing crime rates, incarceration, use of illicit opioids such as heroin or fentanyl, and ultimately marginalization.13 Illegally purchased opioids present many other harms in addition to overdose as they can be injected and may be laced with other substances that increase the risk of harm or overdose. Provision of OAT is often combined with education about harm reduction including use of clean needles and injection supplies in an effort to reduce the risks associated with injection drug use such as contraction of HIV and Hepatitis C and other complications including skin infections, abscesses, or endocarditis.

Structure
Thumb
Synonyms
  • (+-)-Methadone
  • (+/-)-Methadone
  • (±)-methadone
  • 6-Dimethylamino-4,4-diphenyl-3-heptanone
  • dl-Methadone
  • Metadona
  • Methadone
  • Methadonum
Product Ingredients
IngredientUNIICASInChI Key
Methadone hydrochloride229809935B1095-90-5FJQXCDYVZAHXNS-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DisketsTablet40 mg/1OralWest-Ward Pharmaceuticals Corp.1973-03-14Not applicableUs
DolophineTablet10 mg/1OralWest-Ward Pharmaceuticals Corp.1947-08-13Not applicableUs
DolophineTablet5 mg/1OralWest-Ward Pharmaceuticals Corp.1947-08-13Not applicableUs
MetadolTabletOralPaladin Labs Inc2003-07-29Not applicableCanada
MetadolTabletOralPaladin Labs Inc2003-07-29Not applicableCanada
MetadolTabletOralPaladin Labs Inc2003-07-29Not applicableCanada
MetadolSolutionOralPaladin Labs Inc2000-05-05Not applicableCanada
MetadolTabletOralPaladin Labs Inc2003-07-29Not applicableCanada
MetadolSolutionOralPaladin Labs Inc2003-07-11Not applicableCanada
Metadol-DTabletOralPaladin Labs IncNot applicableNot applicableCanada
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Methadone HydrochlorideTablet10 mg/1OralPhysicians Total Care, Inc.2004-01-07Not applicableUs
Methadone hydrochlorideTablet10 mg/1001OralSun Pharmaceutical Industries Limited2018-04-17Not applicableUs
Methadone HydrochlorideTablet10 mg/1OralAurolife Pharma, LLC2015-09-15Not applicableUs
Methadone HydrochlorideSolution5 mg/5mLOralAtlantic Biologicals Corps.1981-05-22Not applicableUs
Methadone HydrochlorideTablet10 mg/1OralVistapharm, Inc.2018-11-22Not applicableUs
Methadone HydrochlorideInjection, solution10 mg/1mLIntramuscular; Intravenous; SubcutaneousAkorn2017-10-30Not applicableUs
Methadone HydrochlorideTablet40 mg/1OralVistapharm, Inc.1998-03-25Not applicableUs
Methadone HydrochlorideTablet10 mg/1OralBlenheim Pharmacal, Inc.2008-06-022011-11-30Us
Methadone HydrochlorideConcentrate10 mg/1mLOralAtlantic Biologicals Corp.2018-10-31Not applicableUs
Methadone HydrochlorideConcentrate10 mg/1mLOralWest-Ward Pharmaceuticals Corp.2010-03-16Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

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International/Other Brands
Adolan / Depridol / Heptadon / Heptanon / Ketalgin / Mephenon / Physeptone
Categories
UNII
UC6VBE7V1Z
CAS number
76-99-3
Weight
Average: 309.4452
Monoisotopic: 309.209264491
Chemical Formula
C21H27NO
InChI Key
USSIQXCVUWKGNF-UHFFFAOYSA-N
InChI
InChI=1S/C21H27NO/c1-5-20(23)21(16-17(2)22(3)4,18-12-8-6-9-13-18)19-14-10-7-11-15-19/h6-15,17H,5,16H2,1-4H3
IUPAC Name
6-(dimethylamino)-4,4-diphenylheptan-3-one
SMILES
CCC(=O)C(CC(C)N(C)C)(C1=CC=CC=C1)C1=CC=CC=C1

Pharmacology

Indication

Methadone is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatment options are inadequate. It's recommended that use is reserved for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.22

Methadone is also indicated for detoxification treatment of opioid addiction (heroin or other morphine-like drugs), and for maintenance substitution treatment for opioid dependence in adults in conjunction with appropriate social and medical services.21,23

Associated Conditions
Pharmacodynamics

Overall, methadone's pharmacological actions result in analgesia, suppression of opioid withdrawal symptoms, sedation, miosis (through binding to receptors in the pupillary muscles), sweating, hypotension, bradycardia, nausea and vomiting (via binding within the chemoreceptor trigger zone), and constipation. Like many basic drugs, methadone also enters mast cells and releases histamine by a non-immunological mechanism leading to flushing, pruritus, and urticaria, which can commonly be misattributed to an allergic reaction.

Compared to other opioids, methadone has fewer active metabolites and therefore a lower risk of neuropsychiatric toxicity. This means that higher doses needed to manage severe pain or addiction are less likely to result in delirium, hyperalgesia, or seizures.19,20

Similar to morphine, both methadone isomers are 5-HT(3) receptor antagonists, although l-methadone produces greater inhibition than d-methadone.

Methadone's effects are reversible by naloxone with a pA2 value similar to its antagonism of morphine.21,22,23

Dependence and Tolerance

As with other opioids, tolerance and physical dependence may develop upon repeated administration of methadone and there is a potential for development of psychological dependence. Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse.

Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning.21,22,23

Cardiac Conduction Effects

Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Cases of QT interval prolongation and serious arrhythmia (torsades de pointes) have been observed during treatment with methadone. These cases appear to be more commonly associated with, but not limited to, higher dose treatment (> 200 mg/day). Methadone should be administered with particular caution to patients already at risk for development of prolonged QT interval (e.g., cardiac hypertrophy, concomitant diuretic use, hypokalemia, hypomagnesemia). Careful monitoring is recommended when using methadone in patients with a history of cardiac conduction disease, those taking medications affecting cardiac conduction, and in other cases where history or physical exam suggest an increased risk of dysrhythmia.21,22,23

Respiratory Depression and Overdose

Serious, life-threatening, or fatal respiratory depression may occur with use of methadone. Patients should be monitored for respiratory depression, especially during initiation of methadone or following a dose increase.

Respiratory depression is of particular concern in elderly or debilitated patients as well as in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation. Methadone should be administered with extreme caution to patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, and CNS depression or coma. In these patients, even usual therapeutic doses of methadone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Alternative, non-opioid analgesics should be considered, and methadone should be employed only under careful medical supervision at the lowest effective dose.

Infants exposed in-utero or through breast milk are at risk of life-threatening respiratory depression upon delivery or when nursed.

Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects, in the short-term use setting. These characteristics can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration.21,22,23

Head Injury and Increased Intracranial Pressure

The respiratory depressant effects of opioids and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a pre-existing increase in intracranial pressure. Furthermore, opioids produce effects which may obscure the clinical course of patients with head injuries. In such patients, methadone must be used with caution, and only if it is deemed essential.21,22,23

Incomplete Cross-tolerance between Methadone and other Opioids

Patients tolerant to other opioids may be incompletely tolerant to methadone. Incomplete cross-tolerance is of particular concern for patients tolerant to other µ-opioid agonists who are being converted to methadone, thus making the determination of dosing during opioid conversion complex. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists. A high degree of “opioid tolerance” does not eliminate the possibility of methadone overdose, iatrogenic or otherwise.21,22,23

Crosstolerance between morphine and methadone has been demonstrated, as steady-state plasma methadone concentrations required for effectiveness (C50%) were higher in abstinent rats previously dosed with morphine, as compared to controls.

Misuse, Abuse, and Diversion of Opioids

Methadone is a mu-agonist opioid with an abuse liability similar to morphine. Methadone, like morphine and other opioids used for analgesia, has the potential for being abused and is subject to criminal diversion.

Methadone can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when dispensing Methadone in situations where the clinician is concerned about an increased risk of misuse, abuse, or diversion.21,22,23

Hypotensive Effect

The administration of methadone may result in severe hypotension in patients whose ability to maintain normal blood pressure is compromised (e.g., severe volume depletion).21,22,23

Gastrointestinal Effects

Methadone and other morphine-like opioids have been shown to decrease bowel motility and cause constipation. This primarily occurs through agonism of opioid receptors in the gut wall. Methadone may obscure the diagnosis or clinical course of patients with acute abdominal conditions.21,22,23

Sexual Function/Reproduction

Reproductive function in human males may be decreased by methadone treatment. Reductions in ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated individuals. In addition, reductions in serum testosterone levels and sperm motility, and abnormalities in sperm morphology have been reported. Long-term use of opioids may be associated with decreased sex hormone levels and symptoms such as low libido, erectile dysfunction, or infertility.21,22,23

Mechanism of action

Methadone is a synthetic opioid analgesic with full agonist activity at the µ-opioid receptor. While agonism of the µ-opioid receptor is the primary mechanism of action for the treatment of pain, methadone also acts as an agonist of κ- and σ-opioid receptors within the central and peripheral nervous systems. Interestingly, methadone differs from morphine (which is considered the gold standard reference opioid) in its antagonism of the N-methyl-D-aspartate (NMDA) receptor and its strong inhibition of serotonin and norepinephrine uptake, which likely also contributes to its antinociceptive activity.2

Methadone is administered as a 50:50 racemic mixture of (R)- and (S)-stereoisomers, with (R)-methadone demonstrating ~10-fold higher affinity and potency for the µ-opioid receptor than the (S) stereoisomer.2 The analgesic activity of the racemate is almost entirely due to the (R)-isomer, while the (S)-isomer lacks significant respiratory depressant activity but does have antitussive effects.

While methadone shares similar effects and risks of other opioids such as morphine, hydromorphone, oxycodone, and fentanyl it has a number of unique pharmacokinetic and pharmacodynamic properties that distinguish it from them and make it a useful agent for the treatment of opioid addiction. For example, methadone abstinence syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe.

TargetActionsOrganism
AMu-type opioid receptor
agonist
Humans
ANMDA receptor
antagonist
Humans
ADelta-type opioid receptor
agonist
Humans
U5-hydroxytryptamine receptor 3A
antagonist
Humans
ANeuronal acetylcholine receptor subunit alpha-7
agonist
Humans
UNeuronal acetylcholine receptor subunit alpha-3
antagonist
Humans
UNeuronal acetylcholine receptor subunit alpha-4
antagonist
Humans
UNeuronal acetylcholine receptor subunit beta-2
antagonist
Humans
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Contraindications

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Absorption

Methadone is one of the more lipid-soluble opioids and is well absorbed from the gastrointestinal tract. Following oral administration of methadone, bioavailability ranges from 36-100%, with a marked interindividual variation. It can be detected in blood as soon as 15-45 minutes following administration with peak plasma concentrations achieved between 1 to 7.5 hours. A second peak is observed ~4 hours after administration and is likely due to enterohepatic circulation. Dose proportionality of methadone pharmacokinetics is not known.2,21,22,23

Following administration of daily oral doses ranging from 10 to 225 mg the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL. Effect of food on the bioavailability of methadone has not been evaluated.2,21,22,23

Slower absorption is observed in opioid users compared to healthy subjects, which may reflect the pharmacological effect of opioids in slowing gastric emptying and mobility.2,21,22,23

Due to the large inter-individual variation in methadone pharmacokinetics and pharmacodynamics, treatment should be individualized to each patient. There was an up to 17-fold interindividual variation found in methadone blood concentrations for a given dosage, likely due in part to individual variability in CYP enzyme function.2 There is also a large variability in pharmacokinetics between methadone's enantiomers, which further complicates pharmacokinetic interpretation and study.8

Volume of distribution

Due to interindividual differences in pharmacokinetics, estimates of methadone's volume of distribution have ranged from 189-470 L8 with monographs listing it between 1.0-8.0L/kg.21,22,23 As this is higher than physiological volumes of total body water, methadone is highly distributed in the body including brain, gut, kidney, liver, muscle, and lung. A population pharmacokinetic study found that subject gender and weight explained ~33% of the variance in the apparent volume of distribution of methadone.2,23

Methadone is found to be secreted in saliva, sweat, breast milk, amniotic fluid and umbilical cord plasma. The concentration in cord blood is about half the maternal levels.23

Protein binding

Methadone is highly bound to plasma proteins. While it primarily binds to α1-acid glycoprotein (85-90%), it also binds to albumin and other tissue and plasma proteins including lipoproteins. Methadone is unusual in the opioid class, in that there is extensive binding to tissue proteins and fairly slow transfer between some parts of this tissue reservoir and the plasma.2,23,11

Metabolism

Methadone undergoes fairly extensive first-pass metabolism. Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, and CYP2C19 and to a lesser extent CYP2C9, CYP2C8, and CYP2D6, are responsible for conversion of methadone to EDDP (2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine) and other inactive metabolites, which are excreted mainly in the urine. Methadone first undergoes N-demethylation to form a highly unstable compound that spontaneously converts to EDDP through cyclization and dehydration. EDDP is then converted to 2-ethyl5-methyl-3,3-diphenyl-1-pyrroline (EDMP). Both EDDP and EDMP are inactive.21,23,11

The CYP isozymes also demonstrate different affinities for metabolizing the different methadone enantiomers: CYP2C19, CYP3A7, and CYP2C8 preferentially metabolize (R)-methadone while CYP2B6, CYP2D6, and CYP2C18 preferentially metabolize (S)-methadone. CYP3A4 does not have an enantiomer preference.9,11

Single nucleotide polymorphisms (SNPs) within the cytochrome P450 enzymes can impact methadone pharmacokinetics and contribute to the interindividual variation in response to methadone therapy. In particular, CYP2B6 polymorphisms have been shown to impact individual response to methadone as it is the predominant determinant involved in the N-demethylation of methadone, clearance, and the metabolic ratios of [methadone]/[EDDP].10 The SNPs CYP2B6*6, *9, *11, CYP2C19*2, *3, CYP3A4*1B, and CYP3A5*3 result in increased methadone plasma concentrations, decreased N-demethylation, and decreased methadone clearance, while homozygous carriers of CYP2B6*6/*6 demonstrate diminished metabolism and clearance of methadone.10 See the pharmacogenomics section for further information.

Pharmacogenomic effects on the CYP enzymes can be significant as the long half-life of methadone can result in some individuals having higher than normal therapeutic levels which puts them at risk of dose-related side effects. For example, elevated (R)-methadone levels can increase the risk of respiratory depression, while elevated (S)-methadone levels can increase the risk of severe cardiac arrhythmias due to prolonged QTc interval.10

Route of elimination

The elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. Unmetabolized methadone and its metabolites are excreted in urine to a variable degree.

Half life

Due to interindividual differences in pharmacokinetics, estimates of methadone's half-life have ranged from 15–207 hours8 with official monographs listing it between 7-59 hours.21,22,23

Clearance

Due to interindividual differences in pharmacokinetics, estimates of methadone's clearance have ranged from 5.9–13 L/h hours8 with approved monographs listing it between 1.4 to 126 L/h.21,22,23

Toxicity

In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur.

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Methadone Action PathwayDrug action
Methadone Metabolism PathwayDrug metabolism
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
ATP-dependent translocase ABCB1---GG2677G > T/Apgx reviewThe ABCB1 2677G > T/A GG genotype affects methadone pharmacokinetics and was associated with a 20% reduction in CL/F.Details
Cytochrome P450 2B6CYP2B6*6Not Available516G >Tpgx reviewThe presence of the rs3745274 minor allele (CYP2B6 515G > T) has been found to affect methadone pharmacokinetics. It reduces CL/F by up to 20% for S-methadone only and reduces (R)- and (S)-methadone N-demethylation,Details
Cytochrome P450 2B6CYP2B6*4Not Availablec.785A>Gpgx reviewThe presence of the rs2279343 allele (CYP2B6 785A>G) amplifies CYP2B6 activity and has been found to increase methadone metabolism and clearance.Details
Cytochrome P450 2B6CYP2B6*2Not Availablec.64C > Tpgx reviewThe presence of the rs8192709 allele has been found to result in a lower metabolic ratio of [Methadone]/[EDDP] in heterozygotes.Details
Cytochrome P450 2B6CYP2B6*5Not Available1459C > Tpgx reviewThere is conflicting evidence for the effects of the presence of the rs3211371 allele (CYP2B6 1459C>T). Some studies show it results in increased CYP2B6 activity and ultimately reduced (S)-methadone plasma levels and increased clearance[A184661] while others have demonstrated the opposite effects. [A184658]Details
Cytochrome P450 2B6CYP2B6*9Not Available516G>TThe presence of the rs3745274 allele (CYP2B6 516G>T) has been shown to reduce CYP2B6 activity, increase (R,S)-methadone plasma levels, and reduce (R)- and (S)-methadone N-demethylation.Details
Cytochrome P450 2B6CYP2B6*11Not Available136A > Gpgx reviewThe presence of the rs35303484 allele (CYP2B6 135A>G) has been shown to increase (S)-methadone plasma levels and decrease clearance.Details
Cytochrome P450 2B6CYP2B6 3′UTRNot Availablec.*1355A > Gpgx reviewThe presence of the rs707265 allele (CYP2B6 c.*1355A>G) has been shown increase the [(S)-MTD/MTD Dose] plasma ratio, and reduce clearance of (S)-methadone.Details
Cytochrome P450 2B6CYP2B6 3′UTRNot Availablec.*1277A > Tpgx reviewThe presence of the rs1038376 allele (CYP2B6 c.*1277A > T) has been shown to increase the [(S)-MTD/MTD Dose] plasma ratio and reduce (S)-MTD clearance.Details
Cytochrome P450 2B6CYP2B6 intron 1Not Availablec.172–468 T > Gpgx reviewThe presence of the rsl0403955 allele (c.172–468 T>G) has been shown increase the [(S)-MTD/MTD Dose] plasma ratio, and reduce clearance of (S)-methadone.Details
Cytochrome P450 2B6CYP2B6 intron 5Not Availablec.923–197T > CThe presence of the rs2279345 allele (CYP2B6 c.923–197T>C) has been shown increase the [(S)-MTD/MTD Dose] plasma ratio, and reduce clearance of (S)-methadone.Details
Cytochrome P450 3A4CYP3A4*1BNot Available−392A > Gpgx reviewThe presence of the rs2740574 allele (CYP3A4 −392A>G) has been shown to increase (S)-methadone plasma levels.Details

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 serum concentration of (R)-warfarin can be increased when it is combined with Methadone.
(S)-WarfarinThe serum concentration of (S)-Warfarin can be increased when it is combined with Methadone.
1-(2-Phenylethyl)-4-phenyl-4-acetoxypiperidineThe metabolism of Methadone can be decreased when combined with 1-(2-Phenylethyl)-4-phenyl-4-acetoxypiperidine.
1,10-PhenanthrolineThe therapeutic efficacy of Methadone can be decreased when used in combination with 1,10-Phenanthroline.
2,5-Dimethoxy-4-ethylamphetamine2,5-Dimethoxy-4-ethylamphetamine may increase the analgesic activities of Methadone.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Methadone is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when Methadone is combined with 4-Bromo-2,5-dimethoxyamphetamine.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Methadone.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when Methadone is combined with 4-Methoxyamphetamine.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Methadone is combined with 5-methoxy-N,N-dimethyltryptamine.
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Food Interactions
  • Take without regard to meals. Avoid alcohol. Usually diluted in fruit juice.

References

Synthesis Reference

Charles J. Barnett, "Modification of methadone synthesis process step." U.S. Patent US4048211, issued August, 1952.

US4048211
General References
  1. Kell MJ: Utilization of plasma and urine methadone concentrations to optimize treatment in maintenance clinics: I. Measurement techniques for a clinical setting. J Addict Dis. 1994;13(1):5-26. [PubMed:8018740]
  2. Eap CB, Buclin T, Baumann P: Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153-93. doi: 10.2165/00003088-200241140-00003. [PubMed:12405865]
  3. Joseph H, Stancliff S, Langrod J: Methadone maintenance treatment (MMT): a review of historical and clinical issues. Mt Sinai J Med. 2000 Oct-Nov;67(5-6):347-64. [PubMed:11064485]
  4. Connock M, Juarez-Garcia A, Jowett S, Frew E, Liu Z, Taylor RJ, Fry-Smith A, Day E, Lintzeris N, Roberts T, Burls A, Taylor RS: Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation. Health Technol Assess. 2007 Mar;11(9):1-171, iii-iv. [PubMed:17313907]
  5. Donny EC, Brasser SM, Bigelow GE, Stitzer ML, Walsh SL: Methadone doses of 100 mg or greater are more effective than lower doses at suppressing heroin self-administration in opioid-dependent volunteers. Addiction. 2005 Oct;100(10):1496-509. [PubMed:16185211]
  6. Haroutiunian S, McNicol ED, Lipman AG: Methadone for chronic non-cancer pain in adults. Cochrane Database Syst Rev. 2012 Nov 14;11:CD008025. doi: 10.1002/14651858.CD008025.pub2. [PubMed:23152251]
  7. 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:7562497]
  8. Bart G, Lenz S, Straka RJ, Brundage RC: Ethnic and genetic factors in methadone pharmacokinetics: a population pharmacokinetic study. Drug Alcohol Depend. 2014 Dec 1;145:185-93. doi: 10.1016/j.drugalcdep.2014.10.014. Epub 2014 Oct 24. [PubMed:25456329]
  9. Wang SC, Ho IK, Tsou HH, Tian JN, Hsiao CF, Chen CH, Tan HK, Lin L, Wu CS, Su LW, Huang CL, Yang YH, Liu ML, Lin KM, Chen CY, Liu SC, Wu HY, Chan HW, Tsai MH, Lin PS, Liu YL: CYP2B6 polymorphisms influence the plasma concentration and clearance of the methadone S-enantiomer. J Clin Psychopharmacol. 2011 Aug;31(4):463-9. doi: 10.1097/JCP.0b013e318222b5dd. [PubMed:21694616]
  10. Ahmad T, Valentovic MA, Rankin GO: Effects of cytochrome P450 single nucleotide polymorphisms on methadone metabolism and pharmacodynamics. Biochem Pharmacol. 2018 Jul;153:196-204. doi: 10.1016/j.bcp.2018.02.020. Epub 2018 Feb 16. [PubMed:29458047]
  11. Volpe DA, Xu Y, Sahajwalla CG, Younis IR, Patel V: Methadone Metabolism and Drug-Drug Interactions: In Vitro and In Vivo Literature Review. J Pharm Sci. 2018 Dec;107(12):2983-2991. doi: 10.1016/j.xphs.2018.08.025. Epub 2018 Sep 8. [PubMed:30205091]
  12. Deng M, Chen SR, Pan HL: Presynaptic NMDA receptors control nociceptive transmission at the spinal cord level in neuropathic pain. Cell Mol Life Sci. 2019 May;76(10):1889-1899. doi: 10.1007/s00018-019-03047-y. Epub 2019 Feb 20. [PubMed:30788514]
  13. Ferri M, Minozzi S, Bo A, Amato L: Slow-release oral morphine as maintenance therapy for opioid dependence. Cochrane Database Syst Rev. 2013 Jun 5;(6):CD009879. doi: 10.1002/14651858.CD009879.pub2. [PubMed:23740540]
  14. Toombs JD, Kral LA: Methadone treatment for pain states. Am Fam Physician. 2005 Apr 1;71(7):1353-8. [PubMed:15832538]
  15. Kahan M, Wilson L, Mailis-Gagnon A, Srivastava A: Canadian guideline for safe and effective use of opioids for chronic noncancer pain: clinical summary for family physicians. Part 2: special populations. Can Fam Physician. 2011 Nov;57(11):1269-76, e419-28. [PubMed:22084456]
  16. Crews JC, Sweeney NJ, Denson DD: Clinical efficacy of methadone in patients refractory to other mu-opioid receptor agonist analgesics for management of terminal cancer pain. Case presentations and discussion of incomplete cross-tolerance among opioid agonist analgesics. Cancer. 1993 Oct 1;72(7):2266-72. doi: 10.1002/1097-0142(19931001)72:7<2266::aid-cncr2820720734>3.0.co;2-p. [PubMed:7690683]
  17. Hewitt DJ: The use of NMDA-receptor antagonists in the treatment of chronic pain. Clin J Pain. 2000 Jun;16(2 Suppl):S73-9. [PubMed:10870744]
  18. Bruera E, Neumann CM: Role of methadone in the management of pain in cancer patients. Oncology (Williston Park). 1999 Sep;13(9):1275-82; discussion 1285-8, 1291. [PubMed:10509323]
  19. Mercadante S: Pathophysiology and treatment of opioid-related myoclonus in cancer patients. Pain. 1998 Jan;74(1):5-9. [PubMed:9514554]
  20. Sarhill N, Davis MP, Walsh D, Nouneh C: Methadone-induced myoclonus in advanced cancer. Am J Hosp Palliat Care. 2001 Jan-Feb;18(1):51-3. doi: 10.1177/104990910101800113. [PubMed:11406880]
  21. FDA Label - Methadone [File]
  22. Health Canada Label - Metadol [File]
  23. Health Canada Label - Methadose [File]
External Links
Human Metabolome Database
HMDB0014477
KEGG Drug
D08195
KEGG Compound
C07163
PubChem Compound
4095
PubChem Substance
46505722
ChemSpider
3953
BindingDB
82507
ChEBI
6807
ChEMBL
CHEMBL651
Therapeutic Targets Database
DAP000267
PharmGKB
PA450401
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Methadone
ATC Codes
N07BC02 — MethadoneN02AC52 — Methadone, combinations excl. psycholeptics
AHFS Codes
  • 28:08.08 — Opiate Agonists
FDA label
Download (327 KB)
MSDS
Download (60 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedTreatmentPain, Acute1
0RecruitingBasic SciencePain1
0RecruitingSupportive CarePostoperative pain1
1CompletedNot AvailableDrug withdrawal syndrome neonatal1
1CompletedNot AvailableHealthy Volunteers1
1CompletedNot AvailableHealthy Volunteers / Pharmacokinetics of Isavuconazole / Pharmacokinetics of Methadone1
1CompletedNot AvailableHepatitis C Viral Infection1
1CompletedNot AvailableInfections, Human Immunodeficiency Virus and Hepatitis1
1CompletedOtherHuman Immunodeficiency Virus (HIV) / Human Immunodeficiency Virus (HIV) Infections1
1CompletedSupportive CareHead and Neck Squamous Cell Carcinoma (HNSCC) / Pain / Stomatitis1
1CompletedSupportive CarePain1
1CompletedTreatmentCocaine Abuse / Opioid Dependence1
1CompletedTreatmentCocaine-Related Disorders / Heroin Dependence / Human Immunodeficiency Virus (HIV)1
1CompletedTreatmentCocaine-Related Disorders / Opiate-Related Disorders1
1CompletedTreatmentHIV Risk Behaviors / Substance-Related Disorders1
1CompletedTreatmentHealthy Volunteers4
1CompletedTreatmentHepatitis C Viral Infection2
1CompletedTreatmentHepatitis C Virus (HCV) Infection1
1CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections3
1CompletedTreatmentCandidiasis infection / Human Immunodeficiency Virus (HIV) Infections1
1CompletedTreatmentMalignancies / Pain1
1CompletedTreatmentMethadone Withdrawal Syndrome / Opioid Dependence2
1Not Yet RecruitingTreatmentIntervertebral Disc Degeneration / Spondylolisthesis, Lumbar Region1
1TerminatedSupportive CareNausea and vomiting / Pain / Sleep disorders and disturbances / Unspecified Adult Solid Tumor, Protocol Specific1
1Unknown StatusBasic ScienceSubstance-Related Disorders1
1WithdrawnTreatmentKyphosis / Scoliosis1
1, 2CompletedBasic ScienceCritically-ill Patients / Premature Birth of Newborn1
1, 2CompletedTreatmentDisease, Chronic / Pain / Prescription Opioid Abuse1
1, 2CompletedTreatmentOpiate Addiction1
1, 2CompletedTreatmentPain1
2CompletedPreventionOpiate Addiction1
2CompletedSupportive CareIdiopathic Scoliosis1
2CompletedTreatmentCocaine-Related Disorders1
2CompletedTreatmentDependence, Cocaine / Opioid Dependence1
2CompletedTreatmentDiabetic Peripheral Neuropathic Pain (DPN)1
2CompletedTreatmentHeroin Dependence / Opioid-Related Disorders / Substance-Related Disorders1
2CompletedTreatmentOpioid Dependence1
2CompletedTreatmentPain2
2RecruitingBasic ScienceMaternal Opioid Use Disorder / Opioid Exposed Infant1
2RecruitingOtherPostoperative pain1
2TerminatedTreatmentDrug withdrawal syndrome neonatal1
2TerminatedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Peripheral neuropathy1
2TerminatedTreatmentMalignancies / Pain2
2TerminatedTreatmentNeoplasms / Pain1
2TerminatedTreatmentOpioid-Related Disorders1
2TerminatedTreatmentPain1
2WithdrawnTreatmentHIV-associated Neuropathy / Polyneuropathies1
2, 3CompletedTreatmentOpioid Dependence1
3CompletedHealth Services ResearchScoliosis1
3CompletedPreventionHepatitis C Viral Infection / Methadone / Substance Dependence1
3CompletedSupportive CarePain1
3CompletedTreatmentChronic Non-Malignant Pain1
3CompletedTreatmentCocaine-Related Disorders / Opioid-Related Disorders / Substance-Related Disorders1
3CompletedTreatmentDrug withdrawal syndrome neonatal / Neonatal Opioid Withdrawal1
3CompletedTreatmentHeroin Addiction1
3CompletedTreatmentHerpes Zoster / Pain1
3CompletedTreatmentHuman Immunodeficiency Virus (HIV)1
3CompletedTreatmentMalignancies1
3CompletedTreatmentOpiate Addiction1
3CompletedTreatmentOpiate Dependent1
3CompletedTreatmentOpioid Dependence3
3CompletedTreatmentOpioid Dependence / Opioid Related Disorders / Pregnancy1
3CompletedTreatmentPost-Herpetic Neuralgia (PHN)1
3Not Yet RecruitingTreatmentFentanyl / Methadone / Morphine / Opiate Substitution Treatment / Opioid-Related Disorders1
3RecruitingSupportive CarePain, Intractable1
3RecruitingTreatmentPain / Scoliosis1
3TerminatedTreatmentCancer, Advanced / Tumors, Solid1
3Unknown StatusTreatmentOpiate Addiction1
3Unknown StatusTreatmentPain Related to Cancer1
4Active Not RecruitingTreatmentPain1
4Active Not RecruitingTreatmentPostoperative pain1
4CompletedPreventionNausea and Vomiting, Postoperative / Postoperative pain1
4CompletedPreventionPain, Chronic / Postoperative pain1
4CompletedTreatmentAcquired Immune Deficiency Syndrome (AIDS) / Human Immunodeficiency Virus (HIV) / Opiate Addiction / Substance, Addiction1
4CompletedTreatmentAcute Postoperative Pain / Chronic Persistent Surgical Pain / Hydromorphone Use / Patients Satisfaction1
4CompletedTreatmentAnaesthesia therapy1
4CompletedTreatmentBack Pain Lower Back1
4CompletedTreatmentCancer of Head and Neck / Pain1
4CompletedTreatmentCollapse of Lumbar Vertebrae / Collapse of Thoracic Vertebra1
4CompletedTreatmentDrug withdrawal syndrome neonatal2
4CompletedTreatmentHeroin Dependence1
4CompletedTreatmentHuman Immunodeficiency Virus (HIV) / Human Immunodeficiency Virus (HIV) Infections / Opioid-Related Disorders1
4CompletedTreatmentHuman Immunodeficiency Virus (HIV) / Substance Related Disorders1
4CompletedTreatmentOpiate Addiction1
4CompletedTreatmentOpiate-Related Disorders1
4CompletedTreatmentPain, Chronic1
4CompletedTreatmentPain, Chronic / Postoperative pain1
4CompletedTreatmentPain, Neuropathic1
4CompletedTreatmentPostoperative pain1
4RecruitingDiagnosticProlonged QT Interval1
4RecruitingHealth Services ResearchAddictions / Hepatitis / Human Immunodeficiency Virus Infection(HIV)/Acquired Immunodeficiency Syndrome (AIDS) / Opioid Dependence / Tuberculosis Infection1
4RecruitingSupportive CareColon Diverticulosis / Colonic Neoplasms / Constipation / Constipation Drug Induced / Diverticulitis, Colonic / Ileus / Ileus paralytic / Ileus; Mechanical / Malignant Neoplasm of Colon / Postoperative pain / Rectum Cancer / Rectum Neoplasm1
4RecruitingTreatmentDrug withdrawal syndrome neonatal1
4RecruitingTreatmentLaminectomy1
4RecruitingTreatmentOpioid Use Disorders1
4RecruitingTreatmentOpioids Use / Postoperative pain1
4RecruitingTreatmentPostoperative pain1
4RecruitingTreatmentQuality of Recovery Scores1
4RecruitingTreatmentThoracolumbar Scoliosis1
4TerminatedTreatmentChronic Hepatitis C Virus (HCV) Infection1
4TerminatedTreatmentNeuropathic Chronic Pain1
4Unknown StatusTreatmentDelirium / Opioid Use, Unspecified With Withdrawal / Opioid-Induced Disorders1
4Unknown StatusTreatmentFracture Bone / Postoperative pain1
4Unknown StatusTreatmentOpioids Use1
Not AvailableActive Not RecruitingHealth Services ResearchOpioid Use Disorders1
Not AvailableActive Not RecruitingOtherOpioid-Related Disorders / Pregnancy1
Not AvailableCompletedNot AvailableAcquired Immune Deficiency Syndrome (AIDS) / Human Immunodeficiency Virus (HIV) Infections / Opiate Dependence / Post Traumatic Stress Disorder (PTSD)1
Not AvailableCompletedNot AvailableCancer Related Pain (Breakthrough Pain) / Pain, Cancer / Pain, Neuropathic / Tumors1
Not AvailableCompletedNot AvailableDelirium / Prolonged QT Interval1
Not AvailableCompletedNot AvailableOpiate Withdrawal Syndrome1
Not AvailableCompletedOtherHealthy Volunteers1
Not AvailableCompletedPreventionHeroin Addiction1
Not AvailableCompletedPreventionPost-Operative Nausea and Vomiting (PONV)1
Not AvailableCompletedTreatmentAnaesthesia therapy / Post-Operative Pain1
Not AvailableCompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
Not AvailableCompletedTreatmentPain1
Not AvailableCompletedTreatmentPain / Spinal Cord Injuries (SCI) / Traumatic Amputations1
Not AvailableCompletedTreatmentPostoperative pain1
Not AvailableRecruitingNot AvailableCardiovascular Disease (CVD) / Human Immunodeficiency Virus (HIV) Infections / Opioid-use Disorder1
Not AvailableRecruitingNot AvailableEmergence Delirium / Strabismus1
Not AvailableRecruitingSupportive CareStage III Cutaneous Squamous Cell Carcinoma of the Head and Neck AJCC v8 / Stage IV Cutaneous Squamous Cell Carcinoma of the Head and Neck AJCC v81
Not AvailableRecruitingTreatmentMalignancies1
Not AvailableRecruitingTreatmentPost Laparotomy Pain Treatment1
Not AvailableRecruitingTreatmentPostoperative pain1
Not AvailableRecruitingTreatmentSickle Cell Disorders1
Not AvailableTerminatedNot AvailableOpioid-Related Disorders1
Not AvailableTerminatedSupportive CareBrain and Central Nervous System Tumors / Chronic Myeloproliferative Disorders / Leukemias / Lymphoproliferative Disorders / Malignant Lymphomas / Multiple Myeloma and Plasma Cell Neoplasm / Myelodysplastic Syndromes / Myelodysplastic/Myeloproliferative Neoplasms / Pain / Precancerous Conditions / Unspecified Adult Solid Tumor, Protocol Specific1
Not AvailableTerminatedTreatmentOpioid Use, Unspecified1
Not AvailableTerminatedTreatmentPostoperative pain1
Not AvailableUnknown StatusNot AvailableOpiate Dependent / Previous Illicit Drug Use1
Not AvailableUnknown StatusDiagnosticPain, Chronic1
Not AvailableUnknown StatusTreatmentHeroin Dependence1
Not AvailableUnknown StatusTreatmentHyperalgesia / Post Operative Pain1
Not AvailableWithdrawnTreatmentOpiate Dependence1
Not AvailableWithdrawnTreatmentPostoperative pain1

Pharmacoeconomics

Manufacturers
  • Roxane laboratories inc
  • Vistapharm inc
  • Mallinckrodt chemical inc
  • Bioniche pharma usa llc
  • Sandoz inc
  • Mallinckrodt inc
  • The pharmanetwork llc
Packagers
  • AAIPharma Inc.
  • Bioniche Pharma
  • Blenheim Pharmacal
  • Bryant Ranch Prepack
  • D.M. Graham Laboratories Inc.
  • Direct Dispensing Inc.
  • Dispensing Solutions
  • Diversified Healthcare Services Inc.
  • Eon Labs
  • Lake Erie Medical and Surgical Supply
  • Mallinckrodt Inc.
  • Nucare Pharmaceuticals Inc.
  • Physicians Total Care Inc.
  • Redpharm Drug
  • Roxane Labs
  • Stat Rx Usa
  • Vistapharm Inc.
  • Xanodyne Pharmaceuticals Inc.
Dosage forms
FormRouteStrength
TabletOral
SolutionOral
Injection, solutionIntravenous10 mg/1mL
TabletOral40 mg/1
ConcentrateOral10 mg/1mL
Injection, solutionIntramuscular; Intravenous; Subcutaneous10 mg/1mL
PowderOral1 g/1g
SolutionOral10 mg/5mL
SolutionOral5 mg/5mL
TabletOral10 mg/1
TabletOral10 mg/1001
TabletOral5 mg/1001
TabletOral5 mg/1
SolutionOral10 mg
Prices
Unit descriptionCostUnit
Methadone hcl 10 mg/ml vial7.48USD ml
Methadone hcl powder5.91USD g
Metadol 25 mg Tablet1.69USD tablet
Metadol 10 mg Tablet0.9USD tablet
Methadone intensol 10 mg/ml0.85USD ml
Metadol 5 mg Tablet0.56USD tablet
Methadone hcl 10 mg tablet0.37USD tablet
Metadol Concentrate 10 mg/ml Liquid0.37USD ml
Methadone hcl 5 mg tablet0.34USD tablet
Dolophine hcl 10 mg tablet0.21USD tablet
Metadol 1 mg Tablet0.17USD tablet
Methadose 5 mg tablet0.16USD tablet
Methadose 10 mg tablet0.14USD tablet
Dolophine hcl 5 mg tablet0.13USD tablet
Metadol 1 mg/ml Solution0.1USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)235.0 °CNot Available
logP3.93HANSCH,C ET AL. (1995)
pKa9.2A497
Predicted Properties
PropertyValueSource
Water Solubility0.0059 mg/mLALOGPS
logP4.14ALOGPS
logP5.01ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)19.79ChemAxon
pKa (Strongest Basic)9.12ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area20.31 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity97.27 m3·mol-1ChemAxon
Polarizability36.28 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9968
Blood Brain Barrier+0.9772
Caco-2 permeable+0.7841
P-glycoprotein substrateSubstrate0.6224
P-glycoprotein inhibitor IInhibitor0.7627
P-glycoprotein inhibitor IINon-inhibitor0.9101
Renal organic cation transporterNon-inhibitor0.5851
CYP450 2C9 substrateNon-substrate0.7822
CYP450 2D6 substrateNon-substrate0.7743
CYP450 3A4 substrateSubstrate0.66
CYP450 1A2 substrateInhibitor0.5312
CYP450 2C9 inhibitorNon-inhibitor0.864
CYP450 2D6 inhibitorInhibitor0.5449
CYP450 2C19 inhibitorNon-inhibitor0.8177
CYP450 3A4 inhibitorNon-inhibitor0.5507
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6586
Ames testNon AMES toxic0.946
CarcinogenicityCarcinogens 0.6315
BiodegradationNot ready biodegradable0.9888
Rat acute toxicity3.5250 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.947
hERG inhibition (predictor II)Inhibitor0.7606
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
GC-MS Spectrum - EI-BGC-MSsplash10-00di-9310000000-d71659ee33e210178a79
GC-MS Spectrum - CI-BGC-MSsplash10-03di-0009000000-c583dd769bf5998ac160
Mass Spectrum (Electron Ionization)MSsplash10-00di-9210000000-7542d8c3f742c7713c13
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/MSsplash10-03di-0029000000-43d5c8da88c1aa260682
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-014i-0090000000-31b8655a24b30962bd8c
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-01b9-0590000000-9894da52e88d32034318
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-014i-0940000000-fedb75bd4c80c6c4fea9
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-0gb9-0940000000-a27b5f75aab7fac8931d
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-014i-0090000000-1d4283f6dffa11b765e7
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-03di-0019000000-416fca50b212d00b968c
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-014i-0090000000-ad95925610aed55afe91
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0aor-1980000000-6d4d0adc4c8db177eaad
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-1920000000-0548504791642aa3b2e0
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-2920000000-dd2ce03c02a54aa24f83
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-3910000000-1af5f56241eabde05700
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-03di-0019000000-015df6e52b9d5ebe5cb2
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-014i-0091000000-b328f3740a7ca4485324
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0aor-0980000000-24074e0b5c722d7279c0
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-1920000000-5477eb89abafab290dd1
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-2920000000-b4ffdf7888e464422c0c
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-0a4i-3910000000-6053da2e4586dbcae300
LC-MS/MS Spectrum - LC-ESI-ITFT , positiveLC-MS/MSsplash10-014i-0090000000-0863c3130ca5df5f25b6

Taxonomy

Description
This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Diphenylmethanes
Direct Parent
Diphenylmethanes
Alternative Parents
Aralkylamines / Gamma-amino ketones / Trialkylamines / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
Diphenylmethane / Aralkylamine / Gamma-aminoketone / Ketone / Tertiary amine / Tertiary aliphatic amine / Carbonyl group / Organooxygen compound / Organonitrogen compound / Amine
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
tertiary amine, benzenes, ketone (CHEBI:6807)

Targets

Details
1. Mu-type opioid receptor
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
Curator comments
Full agonist.
General Function
Voltage-gated calcium channel activity
Specific Function
Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone...
Gene Name
OPRM1
Uniprot ID
P35372
Uniprot Name
Mu-type opioid receptor
Molecular Weight
44778.855 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. Shi J, Hui L, Xu Y, Wang F, Huang W, Hu G: Sequence variations in the mu-opioid receptor gene (OPRM1) associated with human addiction to heroin. Hum Mutat. 2002 Apr;19(4):459-60. [PubMed:11933204]
  4. Kakko J, von Wachenfeldt J, Svanborg KD, Lidstrom J, Barr CS, Heilig M: Mood and neuroendocrine response to a chemical stressor, metyrapone, in buprenorphine-maintained heroin dependence. Biol Psychiatry. 2008 Jan 15;63(2):172-7. Epub 2007 Sep 11. [PubMed:17850768]
  5. Kvam TM, Baar C, Rakvag TT, Kaasa S, Krokan HE, Skorpen F: Genetic analysis of the murine mu opioid receptor: increased complexity of Oprm gene splicing. J Mol Med (Berl). 2004 Apr;82(4):250-5. Epub 2004 Jan 9. [PubMed:14991152]
  6. Eap CB, Buclin T, Baumann P: Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153-93. doi: 10.2165/00003088-200241140-00003. [PubMed:12405865]
  7. Sotgiu ML, Valente M, Storchi R, Caramenti G, Biella GE: Cooperative N-methyl-D-aspartate (NMDA) receptor antagonism and mu-opioid receptor agonism mediate the methadone inhibition of the spinal neuron pain-related hyperactivity in a rat model of neuropathic pain. Pharmacol Res. 2009 Oct;60(4):284-90. doi: 10.1016/j.phrs.2009.04.002. Epub 2009 Apr 11. [PubMed:19717013]
Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Voltage-gated cation channel activity
Specific Function
NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. This protein plays a key role in synaptic p...

Components:
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. Sotgiu ML, Valente M, Storchi R, Caramenti G, Biella GE: Cooperative N-methyl-D-aspartate (NMDA) receptor antagonism and mu-opioid receptor agonism mediate the methadone inhibition of the spinal neuron pain-related hyperactivity in a rat model of neuropathic pain. Pharmacol Res. 2009 Oct;60(4):284-90. doi: 10.1016/j.phrs.2009.04.002. Epub 2009 Apr 11. [PubMed:19717013]
  4. Eap CB, Buclin T, Baumann P: Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153-93. doi: 10.2165/00003088-200241140-00003. [PubMed:12405865]
  5. Hanania T, Manfredi P, Inturrisi C, Vitolo OV: The N-methyl-D-aspartate receptor antagonist d-methadone acutely improves depressive-like behavior in the forced swim test performance of rats. Exp Clin Psychopharmacol. 2019 Aug 1. pii: 2019-44083-001. doi: 10.1037/pha0000310. [PubMed:31368772]
  6. FDA Label - Methadone [File]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Opioid receptor activity
Specific Function
G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine n...
Gene Name
OPRD1
Uniprot ID
P41143
Uniprot Name
Delta-type opioid receptor
Molecular Weight
40368.235 Da
References
  1. Gross ER, Hsu AK, Gross GJ: Acute methadone treatment reduces myocardial infarct size via the delta-opioid receptor in rats during reperfusion. Anesth Analg. 2009 Nov;109(5):1395-402. doi: 10.1213/ANE.0b013e3181b92201. [PubMed:19843777]
  2. Eap CB, Buclin T, Baumann P: Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153-93. doi: 10.2165/00003088-200241140-00003. [PubMed:12405865]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Voltage-gated potassium channel 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. This receptor is a ligand-gate...
Gene Name
HTR3A
Uniprot ID
P46098
Uniprot Name
5-hydroxytryptamine receptor 3A
Molecular Weight
55279.835 Da
References
  1. Deeb TZ, Sharp D, Hales TG: Direct subunit-dependent multimodal 5-hydroxytryptamine3 receptor antagonism by methadone. Mol Pharmacol. 2009 Apr;75(4):908-17. doi: 10.1124/mol.108.053322. Epub 2009 Jan 8. [PubMed:19131665]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Toxic substance binding
Specific Function
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. The cha...
Gene Name
CHRNA7
Uniprot ID
P36544
Uniprot Name
Neuronal acetylcholine receptor subunit alpha-7
Molecular Weight
56448.925 Da
References
  1. Talka R, Tuominen RK, Salminen O: Methadone's effect on nAChRs--a link between methadone use and smoking? Biochem Pharmacol. 2015 Oct 15;97(4):542-549. doi: 10.1016/j.bcp.2015.07.031. Epub 2015 Jul 29. [PubMed:26231941]
  2. Talka R, Salminen O, Tuominen RK: Methadone is a non-competitive antagonist at the alpha4beta2 and alpha3* nicotinic acetylcholine receptors and an agonist at the alpha7 nicotinic acetylcholine receptor. Basic Clin Pharmacol Toxicol. 2015 Apr;116(4):321-8. doi: 10.1111/bcpt.12317. Epub 2014 Oct 7. [PubMed:25196810]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Ligand-gated ion channel activity
Specific Function
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
Gene Name
CHRNA3
Uniprot ID
P32297
Uniprot Name
Neuronal acetylcholine receptor subunit alpha-3
Molecular Weight
57479.54 Da
References
  1. Talka R, Tuominen RK, Salminen O: Methadone's effect on nAChRs--a link between methadone use and smoking? Biochem Pharmacol. 2015 Oct 15;97(4):542-549. doi: 10.1016/j.bcp.2015.07.031. Epub 2015 Jul 29. [PubMed:26231941]
  2. Talka R, Salminen O, Tuominen RK: Methadone is a non-competitive antagonist at the alpha4beta2 and alpha3* nicotinic acetylcholine receptors and an agonist at the alpha7 nicotinic acetylcholine receptor. Basic Clin Pharmacol Toxicol. 2015 Apr;116(4):321-8. doi: 10.1111/bcpt.12317. Epub 2014 Oct 7. [PubMed:25196810]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Ligand-gated ion channel activity
Specific Function
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeabl...
Gene Name
CHRNA4
Uniprot ID
P43681
Uniprot Name
Neuronal acetylcholine receptor subunit alpha-4
Molecular Weight
69956.47 Da
References
  1. Talka R, Tuominen RK, Salminen O: Methadone's effect on nAChRs--a link between methadone use and smoking? Biochem Pharmacol. 2015 Oct 15;97(4):542-549. doi: 10.1016/j.bcp.2015.07.031. Epub 2015 Jul 29. [PubMed:26231941]
  2. Talka R, Salminen O, Tuominen RK: Methadone is a non-competitive antagonist at the alpha4beta2 and alpha3* nicotinic acetylcholine receptors and an agonist at the alpha7 nicotinic acetylcholine receptor. Basic Clin Pharmacol Toxicol. 2015 Apr;116(4):321-8. doi: 10.1111/bcpt.12317. Epub 2014 Oct 7. [PubMed:25196810]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Ligand-gated ion channel activity
Specific Function
After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane permeabl...
Gene Name
CHRNB2
Uniprot ID
P17787
Uniprot Name
Neuronal acetylcholine receptor subunit beta-2
Molecular Weight
57018.575 Da
References
  1. Talka R, Tuominen RK, Salminen O: Methadone's effect on nAChRs--a link between methadone use and smoking? Biochem Pharmacol. 2015 Oct 15;97(4):542-549. doi: 10.1016/j.bcp.2015.07.031. Epub 2015 Jul 29. [PubMed:26231941]
  2. Talka R, Salminen O, Tuominen RK: Methadone is a non-competitive antagonist at the alpha4beta2 and alpha3* nicotinic acetylcholine receptors and an agonist at the alpha7 nicotinic acetylcholine receptor. Basic Clin Pharmacol Toxicol. 2015 Apr;116(4):321-8. doi: 10.1111/bcpt.12317. Epub 2014 Oct 7. [PubMed:25196810]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
Inducer
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...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Kharasch ED, Hoffer C, Whittington D, Sheffels P: Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone. Clin Pharmacol Ther. 2004 Sep;76(3):250-69. [PubMed:15371986]
  2. Boulton DW, Arnaud P, DeVane CL: A single dose of methadone inhibits cytochrome P-4503A activity in healthy volunteers as assessed by the urinary cortisol ratio. Br J Clin Pharmacol. 2001 Apr;51(4):350-4. [PubMed:11318772]
  3. Volpe DA, Xu Y, Sahajwalla CG, Younis IR, Patel V: Methadone Metabolism and Drug-Drug Interactions: In Vitro and In Vivo Literature Review. J Pharm Sci. 2018 Dec;107(12):2983-2991. doi: 10.1016/j.xphs.2018.08.025. Epub 2018 Sep 8. [PubMed:30205091]
  4. Flockhart Table of Drug Interactions [Link]
  5. FDA Label - Methadone [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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. Lan T, Yuan LJ, Hu XX, Zhou Q, Wang J, Huang XX, Dai DP, Cai JP, Hu GX: Effects of CYP2C19 variants on methadone metabolism in vitro. Drug Test Anal. 2017 Apr;9(4):634-639. doi: 10.1002/dta.1997. Epub 2016 May 19. [PubMed:27199033]
  2. Wang SC, Ho IK, Tsou HH, Liu SW, Hsiao CF, Chen CH, Tan HK, Lin L, Wu CS, Su LW, Huang CL, Yang YH, Liu ML, Lin KM, Liu SC, Wu HY, Kuo HW, Chen AC, Chang YS, Liu YL: Functional genetic polymorphisms in CYP2C19 gene in relation to cardiac side effects and treatment dose in a methadone maintenance cohort. OMICS. 2013 Oct;17(10):519-26. doi: 10.1089/omi.2012.0068. Epub 2013 Sep 9. [PubMed:24016178]
  3. Volpe DA, Xu Y, Sahajwalla CG, Younis IR, Patel V: Methadone Metabolism and Drug-Drug Interactions: In Vitro and In Vivo Literature Review. J Pharm Sci. 2018 Dec;107(12):2983-2991. doi: 10.1016/j.xphs.2018.08.025. Epub 2018 Sep 8. [PubMed:30205091]
  4. FDA Label - Methadone [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
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
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
References
  1. Volpe DA, Xu Y, Sahajwalla CG, Younis IR, Patel V: Methadone Metabolism and Drug-Drug Interactions: In Vitro and In Vivo Literature Review. J Pharm Sci. 2018 Dec;107(12):2983-2991. doi: 10.1016/j.xphs.2018.08.025. Epub 2018 Sep 8. [PubMed:30205091]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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. Wu D, Otton SV, Sproule BA, Busto U, Inaba T, Kalow W, Sellers EM: Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone. Br J Clin Pharmacol. 1993 Jan;35(1):30-4. doi: 10.1111/j.1365-2125.1993.tb05666.x. [PubMed:8448065]
  2. Gelston EA, Coller JK, Lopatko OV, James HM, Schmidt H, White JM, Somogyi AA: Methadone inhibits CYP2D6 and UGT2B7/2B4 in vivo: a study using codeine in methadone- and buprenorphine-maintained subjects. Br J Clin Pharmacol. 2012 May;73(5):786-94. doi: 10.1111/j.1365-2125.2011.04145.x. [PubMed:22092298]
  3. Coller JK, Michalakas JR, James HM, Farquharson AL, Colvill J, White JM, Somogyi AA: Inhibition of CYP2D6-mediated tramadol O-demethylation in methadone but not buprenorphine maintenance patients. Br J Clin Pharmacol. 2012 Nov;74(5):835-41. doi: 10.1111/j.1365-2125.2012.04256.x. [PubMed:22369095]
  4. Volpe DA, Xu Y, Sahajwalla CG, Younis IR, Patel V: Methadone Metabolism and Drug-Drug Interactions: In Vitro and In Vivo Literature Review. J Pharm Sci. 2018 Dec;107(12):2983-2991. doi: 10.1016/j.xphs.2018.08.025. Epub 2018 Sep 8. [PubMed:30205091]
  5. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inducer
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Kharasch ED, Hoffer C, Whittington D, Sheffels P: Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone. Clin Pharmacol Ther. 2004 Sep;76(3):250-69. [PubMed:15371986]
  2. Smith HS: Opioid metabolism. Mayo Clin Proc. 2009 Jul;84(7):613-24. doi: 10.1016/S0025-6196(11)60750-7. [PubMed:19567715]
  3. Volpe DA, Xu Y, Sahajwalla CG, Younis IR, Patel V: Methadone Metabolism and Drug-Drug Interactions: In Vitro and In Vivo Literature Review. J Pharm Sci. 2018 Dec;107(12):2983-2991. doi: 10.1016/j.xphs.2018.08.025. Epub 2018 Sep 8. [PubMed:30205091]
  4. Flockhart Table of Drug Interactions [Link]
  5. Opioid Metabolism and Effects of Cytochrome P450 [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Wang JS, DeVane CL: Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro. Drug Metab Dispos. 2003 Jun;31(6):742-7. doi: 10.1124/dmd.31.6.742. [PubMed:12756206]
  2. Kharasch ED: Current Concepts in Methadone Metabolism and Transport. Clin Pharmacol Drug Dev. 2017 Mar;6(2):125-134. doi: 10.1002/cpdd.326. [PubMed:28263461]
  3. Volpe DA, Xu Y, Sahajwalla CG, Younis IR, Patel V: Methadone Metabolism and Drug-Drug Interactions: In Vitro and In Vivo Literature Review. J Pharm Sci. 2018 Dec;107(12):2983-2991. doi: 10.1016/j.xphs.2018.08.025. Epub 2018 Sep 8. [PubMed:30205091]
  4. FDA Label - Methadone [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Catalyzes the formation of aromatic C18 estrogens from C19 androgens.
Gene Name
CYP19A1
Uniprot ID
P11511
Uniprot Name
Aromatase
Molecular Weight
57882.48 Da
References
  1. Lu WJ, Bies R, Kamden LK, Desta Z, Flockhart DA: Methadone: a substrate and mechanism-based inhibitor of CYP19 (aromatase). Drug Metab Dispos. 2010 Aug;38(8):1308-13. doi: 10.1124/dmd.110.032474. Epub 2010 Apr 21. [PubMed:20410453]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Curator comments
Data supporting this enzyme action are limited to in vitro studies.
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. Ferrari A, Coccia CP, Bertolini A, Sternieri E: Methadone--metabolism, pharmacokinetics and interactions. Pharmacol Res. 2004 Dec;50(6):551-9. doi: 10.1016/j.phrs.2004.05.002. [PubMed:15501692]
  2. Prost F, Thormann W: Capillary electrophoresis to assess drug metabolism induced in vitro using single CYP450 enzymes (Supersomes): application to the chiral metabolism of mephenytoin and methadone. Electrophoresis. 2003 Aug;24(15):2577-87. doi: 10.1002/elps.200305493. [PubMed:12900870]
  3. Kapur BM, Hutson JR, Chibber T, Luk A, Selby P: Methadone: a review of drug-drug and pathophysiological interactions. Crit Rev Clin Lab Sci. 2011 Jul-Aug;48(4):171-95. doi: 10.3109/10408363.2011.620601. [PubMed:22035341]
  4. FDA Label - Methadone [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C18
Uniprot ID
P33260
Uniprot Name
Cytochrome P450 2C18
Molecular Weight
55710.075 Da
References
  1. Iribarne C, Berthou F, Baird S, Dreano Y, Picart D, Bail JP, Beaune P, Menez JF: Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. Chem Res Toxicol. 1996 Mar;9(2):365-73. doi: 10.1021/tx950116m. [PubMed:8839037]
  2. Volpe DA, Xu Y, Sahajwalla CG, Younis IR, Patel V: Methadone Metabolism and Drug-Drug Interactions: In Vitro and In Vivo Literature Review. J Pharm Sci. 2018 Dec;107(12):2983-2991. doi: 10.1016/j.xphs.2018.08.025. Epub 2018 Sep 8. [PubMed:30205091]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Rendic S: Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448. [PubMed:11996015]
  2. Kapur BM, Hutson JR, Chibber T, Luk A, Selby P: Methadone: a review of drug-drug and pathophysiological interactions. Crit Rev Clin Lab Sci. 2011 Jul-Aug;48(4):171-95. doi: 10.3109/10408363.2011.620601. [PubMed:22035341]
  3. Volpe DA, Xu Y, Sahajwalla CG, Younis IR, Patel V: Methadone Metabolism and Drug-Drug Interactions: In Vitro and In Vivo Literature Review. J Pharm Sci. 2018 Dec;107(12):2983-2991. doi: 10.1016/j.xphs.2018.08.025. Epub 2018 Sep 8. [PubMed:30205091]
  4. FDA Label - Methadone [File]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Eap CB, Buclin T, Baumann P: Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153-93. doi: 10.2165/00003088-200241140-00003. [PubMed:12405865]
  2. Volpe DA, Xu Y, Sahajwalla CG, Younis IR, Patel V: Methadone Metabolism and Drug-Drug Interactions: In Vitro and In Vivo Literature Review. J Pharm Sci. 2018 Dec;107(12):2983-2991. doi: 10.1016/j.xphs.2018.08.025. Epub 2018 Sep 8. [PubMed:30205091]
Kind
Protein
Organism
Humans
Pharmacological action
No
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Eap CB, Buclin T, Baumann P: Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153-93. doi: 10.2165/00003088-200241140-00003. [PubMed:12405865]
  2. Volpe DA, Xu Y, Sahajwalla CG, Younis IR, Patel V: Methadone Metabolism and Drug-Drug Interactions: In Vitro and In Vivo Literature Review. J Pharm Sci. 2018 Dec;107(12):2983-2991. doi: 10.1016/j.xphs.2018.08.025. Epub 2018 Sep 8. [PubMed:30205091]

Transporters

Details
1. P-glycoprotein 1
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Stormer E, Perloff MD, von Moltke LL, Greenblatt DJ: Methadone inhibits rhodamine123 transport in Caco-2 cells. Drug Metab Dispos. 2001 Jul;29(7):954-6. [PubMed:11408360]
  2. Tournier N, Chevillard L, Megarbane B, Pirnay S, Scherrmann JM, Decleves X: Interaction of drugs of abuse and maintenance treatments with human P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). Int J Neuropsychopharmacol. 2010 Aug;13(7):905-15. doi: 10.1017/S1461145709990848. Epub 2009 Nov 4. [PubMed:19887017]
  3. Eap CB, Buclin T, Baumann P: Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet. 2002;41(14):1153-93. doi: 10.2165/00003088-200241140-00003. [PubMed:12405865]
  4. Volpe DA, Xu Y, Sahajwalla CG, Younis IR, Patel V: Methadone Metabolism and Drug-Drug Interactions: In Vitro and In Vivo Literature Review. J Pharm Sci. 2018 Dec;107(12):2983-2991. doi: 10.1016/j.xphs.2018.08.025. Epub 2018 Sep 8. [PubMed:30205091]

Drug created on June 13, 2005 07:24 / Updated on November 22, 2019 04:03