Details
Stereochemistry | ACHIRAL |
Molecular Formula | C13H8Cl2O4S |
Molecular Weight | 331.171 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
OC(=O)COC1=C(Cl)C(Cl)=C(C=C1)C(=O)C2=CC=CS2
InChI
InChIKey=AGHANLSBXUWXTB-UHFFFAOYSA-N
InChI=1S/C13H8Cl2O4S/c14-11-7(13(18)9-2-1-5-20-9)3-4-8(12(11)15)19-6-10(16)17/h1-5H,6H2,(H,16,17)
Ticrynafen, or tienilic acid, is a diuretic drug with uric acid-lowering action, formerly marketed for the treatment of hypertension. It was withdrawn from the market only months after its introduction because of reports of serious incidents of drug-induced liver injury including some fatalities. Its hepatotoxicity is considered to be primarily immunoallergic in nature. Tienilic acid is a thiophene-containing mechanism-based inactivator of P450 2C9, resulting from covalent modification of the P450 2C9 protein. The bioactivation mechanism involves oxidation of the thiophene ring system.
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: P11712 Gene ID: 1559.0 Gene Symbol: CYP2C9 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/18838506 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | SELACRYN Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
10.1 mg/dL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7398677 |
1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered: |
TICRYNAFEN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
2.48 mg/dL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7398677 |
250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered: |
TICRYNAFEN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
4.48 mg/dL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7398677 |
500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered: |
TICRYNAFEN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1.56 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7398677 |
250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered: |
TICRYNAFEN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
2.43 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7398677 |
500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered: |
TICRYNAFEN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
2% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7398677 |
1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered: |
TICRYNAFEN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
2% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7398677 |
250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered: |
TICRYNAFEN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
2% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7398677 |
500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered: |
TICRYNAFEN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
250 mg 1 times / day multiple, oral Recommended Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: |
unhealthy, 30-69 years n = 3 Health Status: unhealthy Condition: arterial hypertension Age Group: 30-69 years Sex: M Population Size: 3 Sources: |
Disc. AE: Back pain, Prothrombin time increased... AEs leading to discontinuation/dose reduction: Back pain (severe, 1 patient) Sources: Prothrombin time increased (grade 5, 1 patient) Partial thromboplastin time prolonged (grade 5, 1 patient) |
250 mg 1 times / day multiple, oral Recommended Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: |
unhealthy n = 57 |
Disc. AE: Hepatotoxicity... AEs leading to discontinuation/dose reduction: Hepatotoxicity Sources: |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Partial thromboplastin time prolonged | grade 5, 1 patient Disc. AE |
250 mg 1 times / day multiple, oral Recommended Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: |
unhealthy, 30-69 years n = 3 Health Status: unhealthy Condition: arterial hypertension Age Group: 30-69 years Sex: M Population Size: 3 Sources: |
Prothrombin time increased | grade 5, 1 patient Disc. AE |
250 mg 1 times / day multiple, oral Recommended Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: |
unhealthy, 30-69 years n = 3 Health Status: unhealthy Condition: arterial hypertension Age Group: 30-69 years Sex: M Population Size: 3 Sources: |
Back pain | severe, 1 patient Disc. AE |
250 mg 1 times / day multiple, oral Recommended Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: |
unhealthy, 30-69 years n = 3 Health Status: unhealthy Condition: arterial hypertension Age Group: 30-69 years Sex: M Population Size: 3 Sources: |
Hepatotoxicity | Disc. AE | 250 mg 1 times / day multiple, oral Recommended Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: |
unhealthy n = 57 |
PubMed
Title | Date | PubMed |
---|---|---|
Immune-mediated drug-induced liver disease. | 2002 Aug |
|
Effects of novel ethacrynic acid derivatives on human trabecular meshwork cell shape, actin cytoskeletal organization, and transcellular fluid flow. | 2005 Dec |
|
Automated assessment of time-dependent inhibition of human cytochrome P450 enzymes using liquid chromatography-tandem mass spectrometry analysis. | 2005 Nov |
|
Ethanol oxidation into acetaldehyde by 16 recombinant human cytochrome P450 isoforms: role of CYP2C isoforms in human liver microsomes. | 2006 Dec 15 |
|
Toxicological significance of mechanism-based inactivation of cytochrome p450 enzymes by drugs. | 2007 Jun |
|
The crucial protective role of glutathione against tienilic acid hepatotoxicity in rats. | 2008 Oct 15 |
|
Can in vitro metabolism-dependent covalent binding data in liver microsomes distinguish hepatotoxic from nonhepatotoxic drugs? An analysis of 18 drugs with consideration of intrinsic clearance and daily dose. | 2008 Sep |
|
Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. | 2009 |
|
Prediction of pharmacological and xenobiotic responses to drugs based on time course gene expression profiles. | 2009 Dec 2 |
|
CYP2C9-mediated metabolic activation of losartan detected by a highly sensitive cell-based screening assay. | 2011 May |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/319271
In a double-blind study, 20 hypertensive patients were randomly assigned to a six-week regimen of either ticrynafen or hydrochlorothiazide. Blood pressure was significantly reduced with both medications, although most patients required an increase in dosage from 250 to 500 mg ticrynafen daily.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/18838506
Human recombinant P450 2C9 was assayed for residual activity with probe substrate [(S)-flurbiprofen, diclofenac, or (S)-warfarin] after a primary incubation with various concentrations of tienilic acid, analog 1, or (±)-suprofen (0.5% total organic v/v) in triplicate in a 96-well plate format at 37°C. Inactivation by tienilic acid and (±)-suprofen was described by comparable kinact and KI values against P450 2C9-mediated (S)-flurbiprofen and diclofenac hydroxylation. Inactivation of (S)-warfarin 7-hydroxylation by both tienilic acid and (±)-suprofen was best fit to a standard hyperbolic equation, which yielded noticeably lower KI estimates [12.5 and 6.7 μM with tienilic acid and (±)-suprofen, respectively], resulting in moderately higher inactivation efficiencies, in particular for (±)-suprofen. Tienilic acid was a markedly better inactivator of P450 2C9 compared with (±)-suprofen, independent of probe substrate, with a 4- to 8-fold higher inactivation efficiency.
Name | Type | Language | ||
---|---|---|---|---|
|
Official Name | English | ||
|
Official Name | English | ||
|
Code | English | ||
|
Common Name | English | ||
|
Code | English | ||
|
Common Name | English | ||
|
Common Name | English | ||
|
Common Name | English | ||
|
Common Name | English | ||
|
Brand Name | English |
Classification Tree | Code System | Code | ||
---|---|---|---|---|
|
WHO-ATC |
C03CC02
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
||
|
WHO-VATC |
QC03CC02
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
||
|
NCI_THESAURUS |
C921
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
||
|
NCI_THESAURUS |
C49184
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
Code System | Code | Type | Description | ||
---|---|---|---|---|---|
|
3036
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
PRIMARY | |||
|
40180-04-9
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
PRIMARY | |||
|
SUB11032MIG
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
PRIMARY | |||
|
HC95205SY4
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
PRIMARY | |||
|
D013989
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
PRIMARY | |||
|
m10856
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
PRIMARY | Merck Index | ||
|
Tienilic acid
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
PRIMARY | |||
|
2658
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
PRIMARY | |||
|
254-826-3
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
PRIMARY | |||
|
DTXSID4023670
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
PRIMARY | |||
|
38409
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
PRIMARY | |||
|
C152613
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
PRIMARY | |||
|
DB04831
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
PRIMARY | |||
|
100000082169
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
PRIMARY | |||
|
CHEMBL267744
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
PRIMARY | |||
|
9590
Created by
admin on Fri Dec 15 15:14:22 GMT 2023 , Edited by admin on Fri Dec 15 15:14:22 GMT 2023
|
PRIMARY |
ACTIVE MOIETY
SALT/SOLVATE (PARENT)