U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C14H23NO
Molecular Weight 221.3385
Optical Activity ( - )
Defined Stereocenters 2 / 2
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of TAPENTADOL

SMILES

CC[C@H]([C@@H](C)CN(C)C)C1=CC=CC(O)=C1

InChI

InChIKey=KWTWDQCKEHXFFR-SMDDNHRTSA-N
InChI=1S/C14H23NO/c1-5-14(11(2)10-15(3)4)12-7-6-8-13(16)9-12/h6-9,11,14,16H,5,10H2,1-4H3/t11-,14+/m0/s1

HIDE SMILES / InChI

Molecular Formula C14H23NO
Molecular Weight 221.3385
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 2 / 2
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/21476608 | https://www.nucynta.com/hcp/er/mechanism-of-action#isi-0

Tapentadol is the first US FDA-approved centrally acting analgesic having both μ-opioid receptor agonist and noradrenaline (norepinephrine) reuptake inhibition activity with minimal serotonin reuptake inhibition. Tapentadol is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate, neuropathic pain associated with diabetic peripheral neuropathy (DPN) severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
0.16 µM [Ki]
8.8 µM [Ki]
5.28 µM [Ki]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
NUCYNTA

Approved Use

NUCYNTA ER (tapentadol) is indicated for the management of: pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate neuropathic pain associated with diabetic peripheral neuropathy (DPN) severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Launch Date

2008
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
221.34 ng/mL
86 mg single, oral
dose: 86 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TAPENTADOL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
221.34 ng × h/mL
86 mg single, oral
dose: 86 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TAPENTADOL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
1.16 h
86 mg single, oral
dose: 86 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TAPENTADOL plasma
Homo sapiens
population: HEALTHY
age: ADULT
sex: MALE
food status: FASTED
4 h
100 mg single, oral
dose: 100 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TAPENTADOL plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
80%
100 mg single, oral
dose: 100 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
TAPENTADOL plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
250 mg 2 times / day multiple, oral (max)
Recommended
Dose: 250 mg, 2 times / day
Route: oral
Route: multiple
Dose: 250 mg, 2 times / day
Sources: Page: p.424
unhealthy, 56.8
n = 894
Health Status: unhealthy
Condition: Chronic low back pain|Osteoarthritis pain
Age Group: 56.8
Sex: M+F
Population Size: 894
Sources: Page: p.424
Disc. AE: Nausea, Constipation...
AEs leading to
discontinuation/dose reduction:
Nausea (3.4%)
Constipation (1.6%)
Dizziness (3%)
Vomiting (2.6%)
Fatigue (1.8%)
Somnolence (3.4%)
Pruritus (0.6%)
Sources: Page: p.424
100 mg 6 times / day multiple, oral
Recommended
Dose: 100 mg, 6 times / day
Route: oral
Route: multiple
Dose: 100 mg, 6 times / day
Sources: Page: p.7
unhealthy
Health Status: unhealthy
Condition: Acute pain
Sources: Page: p.7
Disc. AE: Dizziness, Nausea...
AEs leading to
discontinuation/dose reduction:
Dizziness
Nausea
Vomiting
Somnolence
Headache
Sources: Page: p.7
700 mg 6 times / day multiple, oral (total)
Recommended
Dose: 700 mg, 6 times / day
Route: oral
Route: multiple
Dose: 700 mg, 6 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: Acute pain
Sources: Page: p.1
Disc. AE: Respiratory depression, CNS disorder (NOS)...
AEs leading to
discontinuation/dose reduction:
Respiratory depression
CNS disorder (NOS)
Intracranial pressure increased
Abuse NOS
Mental function decreased
Physical impairment
Seizures
Serotonin syndrome (grade 4)
Sources: Page: p.1
AEs

AEs

AESignificanceDosePopulation
Pruritus 0.6%
Disc. AE
250 mg 2 times / day multiple, oral (max)
Recommended
Dose: 250 mg, 2 times / day
Route: oral
Route: multiple
Dose: 250 mg, 2 times / day
Sources: Page: p.424
unhealthy, 56.8
n = 894
Health Status: unhealthy
Condition: Chronic low back pain|Osteoarthritis pain
Age Group: 56.8
Sex: M+F
Population Size: 894
Sources: Page: p.424
Constipation 1.6%
Disc. AE
250 mg 2 times / day multiple, oral (max)
Recommended
Dose: 250 mg, 2 times / day
Route: oral
Route: multiple
Dose: 250 mg, 2 times / day
Sources: Page: p.424
unhealthy, 56.8
n = 894
Health Status: unhealthy
Condition: Chronic low back pain|Osteoarthritis pain
Age Group: 56.8
Sex: M+F
Population Size: 894
Sources: Page: p.424
Fatigue 1.8%
Disc. AE
250 mg 2 times / day multiple, oral (max)
Recommended
Dose: 250 mg, 2 times / day
Route: oral
Route: multiple
Dose: 250 mg, 2 times / day
Sources: Page: p.424
unhealthy, 56.8
n = 894
Health Status: unhealthy
Condition: Chronic low back pain|Osteoarthritis pain
Age Group: 56.8
Sex: M+F
Population Size: 894
Sources: Page: p.424
Vomiting 2.6%
Disc. AE
250 mg 2 times / day multiple, oral (max)
Recommended
Dose: 250 mg, 2 times / day
Route: oral
Route: multiple
Dose: 250 mg, 2 times / day
Sources: Page: p.424
unhealthy, 56.8
n = 894
Health Status: unhealthy
Condition: Chronic low back pain|Osteoarthritis pain
Age Group: 56.8
Sex: M+F
Population Size: 894
Sources: Page: p.424
Dizziness 3%
Disc. AE
250 mg 2 times / day multiple, oral (max)
Recommended
Dose: 250 mg, 2 times / day
Route: oral
Route: multiple
Dose: 250 mg, 2 times / day
Sources: Page: p.424
unhealthy, 56.8
n = 894
Health Status: unhealthy
Condition: Chronic low back pain|Osteoarthritis pain
Age Group: 56.8
Sex: M+F
Population Size: 894
Sources: Page: p.424
Nausea 3.4%
Disc. AE
250 mg 2 times / day multiple, oral (max)
Recommended
Dose: 250 mg, 2 times / day
Route: oral
Route: multiple
Dose: 250 mg, 2 times / day
Sources: Page: p.424
unhealthy, 56.8
n = 894
Health Status: unhealthy
Condition: Chronic low back pain|Osteoarthritis pain
Age Group: 56.8
Sex: M+F
Population Size: 894
Sources: Page: p.424
Somnolence 3.4%
Disc. AE
250 mg 2 times / day multiple, oral (max)
Recommended
Dose: 250 mg, 2 times / day
Route: oral
Route: multiple
Dose: 250 mg, 2 times / day
Sources: Page: p.424
unhealthy, 56.8
n = 894
Health Status: unhealthy
Condition: Chronic low back pain|Osteoarthritis pain
Age Group: 56.8
Sex: M+F
Population Size: 894
Sources: Page: p.424
Dizziness Disc. AE
100 mg 6 times / day multiple, oral
Recommended
Dose: 100 mg, 6 times / day
Route: oral
Route: multiple
Dose: 100 mg, 6 times / day
Sources: Page: p.7
unhealthy
Health Status: unhealthy
Condition: Acute pain
Sources: Page: p.7
Headache Disc. AE
100 mg 6 times / day multiple, oral
Recommended
Dose: 100 mg, 6 times / day
Route: oral
Route: multiple
Dose: 100 mg, 6 times / day
Sources: Page: p.7
unhealthy
Health Status: unhealthy
Condition: Acute pain
Sources: Page: p.7
Nausea Disc. AE
100 mg 6 times / day multiple, oral
Recommended
Dose: 100 mg, 6 times / day
Route: oral
Route: multiple
Dose: 100 mg, 6 times / day
Sources: Page: p.7
unhealthy
Health Status: unhealthy
Condition: Acute pain
Sources: Page: p.7
Somnolence Disc. AE
100 mg 6 times / day multiple, oral
Recommended
Dose: 100 mg, 6 times / day
Route: oral
Route: multiple
Dose: 100 mg, 6 times / day
Sources: Page: p.7
unhealthy
Health Status: unhealthy
Condition: Acute pain
Sources: Page: p.7
Vomiting Disc. AE
100 mg 6 times / day multiple, oral
Recommended
Dose: 100 mg, 6 times / day
Route: oral
Route: multiple
Dose: 100 mg, 6 times / day
Sources: Page: p.7
unhealthy
Health Status: unhealthy
Condition: Acute pain
Sources: Page: p.7
Abuse NOS Disc. AE
700 mg 6 times / day multiple, oral (total)
Recommended
Dose: 700 mg, 6 times / day
Route: oral
Route: multiple
Dose: 700 mg, 6 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: Acute pain
Sources: Page: p.1
CNS disorder (NOS) Disc. AE
700 mg 6 times / day multiple, oral (total)
Recommended
Dose: 700 mg, 6 times / day
Route: oral
Route: multiple
Dose: 700 mg, 6 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: Acute pain
Sources: Page: p.1
Intracranial pressure increased Disc. AE
700 mg 6 times / day multiple, oral (total)
Recommended
Dose: 700 mg, 6 times / day
Route: oral
Route: multiple
Dose: 700 mg, 6 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: Acute pain
Sources: Page: p.1
Mental function decreased Disc. AE
700 mg 6 times / day multiple, oral (total)
Recommended
Dose: 700 mg, 6 times / day
Route: oral
Route: multiple
Dose: 700 mg, 6 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: Acute pain
Sources: Page: p.1
Physical impairment Disc. AE
700 mg 6 times / day multiple, oral (total)
Recommended
Dose: 700 mg, 6 times / day
Route: oral
Route: multiple
Dose: 700 mg, 6 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: Acute pain
Sources: Page: p.1
Respiratory depression Disc. AE
700 mg 6 times / day multiple, oral (total)
Recommended
Dose: 700 mg, 6 times / day
Route: oral
Route: multiple
Dose: 700 mg, 6 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: Acute pain
Sources: Page: p.1
Seizures Disc. AE
700 mg 6 times / day multiple, oral (total)
Recommended
Dose: 700 mg, 6 times / day
Route: oral
Route: multiple
Dose: 700 mg, 6 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: Acute pain
Sources: Page: p.1
Serotonin syndrome grade 4
Disc. AE
700 mg 6 times / day multiple, oral (total)
Recommended
Dose: 700 mg, 6 times / day
Route: oral
Route: multiple
Dose: 700 mg, 6 times / day
Sources: Page: p.1
unhealthy
Health Status: unhealthy
Condition: Acute pain
Sources: Page: p.1
Overview

OverviewOther

Other InhibitorOther SubstrateOther Inducer






Drug as perpetrator​Drug as victimTox targets

Tox targets

TargetModalityActivityMetaboliteClinical evidence
PubMed

PubMed

TitleDatePubMed
Absorption, metabolism, and excretion of 14C-labeled tapentadol HCl in healthy male subjects.
2007 Jul-Sep
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties.
2007 Oct
Investigations into the drug-drug interaction potential of tapentadol in human liver microsomes and fresh human hepatocytes.
2008 Jan
Tapentadol a 'realistic alternative' to strong opioids for severe pain.
2008 Sep
Tapentadol (Nucynta)--a new analgesic.
2009 Aug 10
Tapentadol approved as pain reliever.
2009 Jan 1
Tapentadol hydrochloride: a next-generation, centrally acting analgesic with two mechanisms of action in a single molecule.
2009 Jul
Is tapentadol an advance on tramadol?
2009 Nov
Tapentadol immediate release for the relief of moderate-to-severe acute pain.
2009 Nov
Efficacy and safety of Tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee: a randomized, double-blind, placebo- and active-controlled phase III study.
2010
Tapentadol for acute and chronic pain.
2010 Aug
Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled Phase III study.
2010 Aug
Tapentadol, but not morphine, selectively inhibits disease-related thermal hyperalgesia in a mouse model of diabetic neuropathic pain.
2010 Feb 12
Stereochemical basis for a unified structure activity theory of aromatic and heterocyclic rings in selected opioids and opioid peptides.
2010 Feb 18
Effects of acetaminophen, naproxen, and acetylsalicylic acid on tapentadol pharmacokinetics: results of two randomized, open-label, crossover, drug-drug interaction studies.
2010 Jan
In vitro and in vivo characterization of tapentadol metabolites.
2010 Jan-Feb
Review of the effect of opioid-related side effects on the undertreatment of moderate to severe chronic non-cancer pain: tapentadol, a step toward a solution?
2010 Jul
Efficacy and safety of tapentadol prolonged release for chronic osteoarthritis pain and low back pain.
2010 Jun
Recent advances in postoperative pain management.
2010 Mar
Tapentadol: an initial analysis.
2010 May-Jun
Evaluation of study discontinuations with tapentadol inmmediate release and oxycodone immediate release in patients with low back or osteoarthritis pain.
2010 May-Jun
Determination of tapentadol (Nucynta®) and N-desmethyltapentadol in authentic urine specimens by ultra-performance liquid chromatography-tandem mass spectrometry.
2010 Oct
Analgesic update: tapentadol hydrochloride.
2010 Oct
Population pharmacokinetics of tapentadol immediate release (IR) in healthy subjects and patients with moderate or severe pain.
2010 Oct
Tapentadol and its two mechanisms of action: is there a new pharmacological class of centrally-acting analgesics on the horizon?
2010 Sep
Differential contribution of opioid and noradrenergic mechanisms of tapentadol in rat models of nociceptive and neuropathic pain.
2010 Sep
Tapentadol immediate release: a review of its use in the treatment of moderate to severe acute pain.
2010 Sep 10
Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain.
2010 Sep-Oct
Comparative pharmacokinetics and bioavailability of tapentadol following oral administration of immediate- and prolonged-release formulations.
2013 Apr
Tapentadol hydrochloride: A novel analgesic.
2013 Jul
Patents

Sample Use Guides

As with many centrally-acting analgesic medications, the dosing regimen of NUCYNTA® should be individualized according to the severity of pain being treated, the previous experience with similar drugs and the ability to monitor the patient. Initiate NUCYNTA® with or without food at a dose of 50 mg, 75 mg, or 100 mg every 4 to 6 hours depending upon pain intensity. On the first day of dosing, the second dose may be administered as soon as one hour after the first dose, if adequate pain relief is not attained with the first dose. Subsequent dosing is 50 mg, 75 mg, or 100 mg every 4 to 6 hours and should be adjusted to maintain adequate analgesia with acceptable tolerability. Daily doses greater than 700 mg on the first day of therapy and 600 mg on subsequent days have not been studied and are, therefore, not recommended.
Route of Administration: Oral
Upon exposure to tramadol and tapentadol concentrations up to 600μM, cell toxicity was assessed through evaluation of oxidative stress, mitochondrial and metabolic alterations, as well as cell viability and death mechanisms through necrosis or apoptosis, and related signalling. Tapentadol was observed to trigger much more prominent toxic effects than tramadol, ultimately leading to energy deficit and cell death.
Substance Class Chemical
Created
by admin
on Fri Dec 15 16:27:08 GMT 2023
Edited
by admin
on Fri Dec 15 16:27:08 GMT 2023
Record UNII
H8A007M585
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
TAPENTADOL
DASH   INN   MART.   MI   USAN   VANDF   WHO-DD  
INN   USAN  
Official Name English
TAPENTADOL [USAN]
Common Name English
3-[(1R,2R)-3-(Dimethylamino)-1-ethyl-2-methylpropyl]phenol
Systematic Name English
tapentadol [INN]
Common Name English
TAPENTADOL [VANDF]
Common Name English
NSC-759619
Code English
PHENOL, 3-((1R,2R)-3-(DIMETHYLAMINO)-1-ETHYL-2-METHYLPROPYL)-
Systematic Name English
CG-5503
Code English
CG5503 IR
Code English
BN-200
Code English
TAPENTADOL [MI]
Common Name English
TAPENTADOL [MART.]
Common Name English
Tapentadol [WHO-DD]
Common Name English
CG5503
Code English
Classification Tree Code System Code
NDF-RT N0000175690
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
NCI_THESAURUS C241
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
WHO-VATC QN02AX06
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
WHO-ATC N02AX06
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
LIVERTOX 923
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
DEA NO. 9780
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
NDF-RT N0000000174
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
Code System Code Type Description
IUPHAR
7477
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
PRIMARY
HSDB
8309
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
PRIMARY
NCI_THESAURUS
C72139
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PRIMARY
EPA CompTox
DTXSID30170003
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
PRIMARY
NSC
759619
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PRIMARY
DRUG BANK
DB06204
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
PRIMARY
MERCK INDEX
m10459
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
PRIMARY Merck Index
PUBCHEM
9838022
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PRIMARY
DRUG CENTRAL
4283
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PRIMARY
CAS
175591-23-8
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
PRIMARY
LACTMED
Tapentadol
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
PRIMARY
DAILYMED
H8A007M585
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
PRIMARY
WIKIPEDIA
TAPENTADOL
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
PRIMARY
FDA UNII
H8A007M585
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
PRIMARY
USAN
QQ-108
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
PRIMARY
EVMPD
SUB31821
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
PRIMARY
MESH
C523979
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PRIMARY
INN
8216
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PRIMARY
SMS_ID
100000124502
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
PRIMARY
ChEMBL
CHEMBL1201776
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
PRIMARY
RXCUI
787390
Created by admin on Fri Dec 15 16:27:08 GMT 2023 , Edited by admin on Fri Dec 15 16:27:08 GMT 2023
PRIMARY RxNorm
Related Record Type Details
BINDER->LIGAND
TARGET -> AGONIST
SALT/SOLVATE -> PARENT
SALT/SOLVATE -> PARENT
TARGET -> INHIBITOR
SALT/SOLVATE -> PARENT
SALT/SOLVATE -> PARENT
BINDER->LIGAND
BINDING
TARGET -> INHIBITOR
SALT/SOLVATE -> PARENT
Related Record Type Details
METABOLITE -> PARENT
In vitro and in vivo
METABOLITE INACTIVE -> PARENT
MAJOR
PLASMA
METABOLITE INACTIVE -> PARENT
no clinically relevant active metabolites
MINOR
URINE
METABOLITE INACTIVE -> PARENT
MAJOR
PLASMA
METABOLITE INACTIVE -> PARENT
METABOLITE INACTIVE -> PARENT
URINE
METABOLITE INACTIVE -> PARENT
No active metabolites of Tapentadol
URINE
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Volume of Distribution PHARMACOKINETIC
Biological Half-life PHARMACOKINETIC