Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C13H8Cl2O4S.C4H11NO3 |
| Molecular Weight | 452.306 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
NC(CO)(CO)CO.OC(=O)COC1=C(Cl)C(Cl)=C(C=C1)C(=O)C2=CC=CS2
InChI
InChIKey=QGUZMWVXVNOEMD-UHFFFAOYSA-N
InChI=1S/C13H8Cl2O4S.C4H11NO3/c14-11-7(13(18)9-2-1-5-20-9)3-4-8(12(11)15)19-6-10(16)17;5-4(1-6,2-7)3-8/h1-5H,6H2,(H,16,17);6-8H,1-3,5H2
| Molecular Formula | C13H8Cl2O4S |
| Molecular Weight | 331.171 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Optical Activity | NONE |
| Molecular Formula | C4H11NO3 |
| Molecular Weight | 121.135 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ACHIRAL |
| Additional Stereochemistry | No |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Optical Activity | NONE |
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 It was withdrawn from the market only months after its introduction because of reports of serious incidents of drug-induced liver injury including some fatalities.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
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 |
|---|---|---|
| Adverse reactions associated with ticrynafen use. | 1980 Feb 22-29 |
|
| Tienilic acid in the treatment of mild to moderate hypertension. | 1980 Sep-Oct |
|
| Drug-induced hepatitis associated with anticytoplasmic organelle autoantibodies. | 1985 Sep-Oct |
|
| Human cytochrome P450 2E1 is a major autoantigen associated with halothane hepatitis. | 1996 Oct-Nov |
|
| Ticlopidine as a selective mechanism-based inhibitor of human cytochrome P450 2C19. | 2001 Oct 9 |
|
| Substrate selectivity of human cytochrome P450 2C9: importance of residues 476, 365, and 114 in recognition of diclofenac and sulfaphenazole and in mechanism-based inactivation by tienilic acid. | 2003 Jan 1 |
|
| Cytochrome P450 and liver diseases. | 2004 Jun |
|
| Screening procedure for detection of diuretics and uricosurics and/or their metabolites in human urine using gas chromatography-mass spectrometry after extractive methylation. | 2005 Aug |
|
| Automated screening with confirmation of mechanism-based inactivation of CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP1A2 in pooled human liver microsomes. | 2005 Aug |
|
| Effects of novel ethacrynic acid derivatives on human trabecular meshwork cell shape, actin cytoskeletal organization, and transcellular fluid flow. | 2005 Dec |
|
| Toxicological significance of mechanism-based inactivation of cytochrome p450 enzymes by drugs. | 2007 Jun |
|
| A novel approach to cyclin-dependent kinase 5/p25 inhibitors: A potential treatment for Alzheimer's disease. | 2007 Oct 1 |
|
| A generic method to detect electrophilic intermediates using isotopic pattern triggered data-dependent high-resolution accurate mass spectrometry. | 2008 Apr |
|
| 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 |
|
| Evaluation of the potential for drug-induced liver injury based on in vitro covalent binding to human liver proteins. | 2009 Dec |
|
| Mechanism-based inactivation of cytochrome P450 2C9 by tienilic acid and (+/-)-suprofen: a comparison of kinetics and probe substrate selection. | 2009 Jan |
|
| Cocktail-substrate assay system for mechanism-based inhibition of CYP2C9, CYP2D6, and CYP3A using human liver microsomes at an early stage of drug development. | 2009 Jun |
|
| CYP2C9-mediated metabolic activation of losartan detected by a highly sensitive cell-based screening assay. | 2011 May |
|
| Differential oxidation of two thiophene-containing regioisomers to reactive metabolites by cytochrome P450 2C9. | 2012 Apr 16 |
Patents
Sample Use Guides
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
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.
| Substance Class |
Chemical
Created
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| Record UNII |
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| Record Status |
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