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Drug

D0122 | Tolfenamic Acid

Molecular Formula C14H12ClNO2
Molecular Weight 261.7
Structure
State solid
Clearance The estimated clearance rate of tolfenamic acid is 0.142-0.175 L.h/kg.[A31842] When tested intravenously, the reported clearance rate was 72.4 ml.h/kg.[A31849]
Volume of distribution The volume of distribution is of 1.79-3.2 L/kg.[A31842] When tested intravenously, the reported steady-state volume of distribution was 0.33 L/kg.[A31849]
Route of elimination Tolfenamic acid is cleared relatively fast and it undergoes by hepatic metabolism where the produced metabolites are renally cleared as glucuronic acid conjugates.[A31851] Most of the elimination occurs by extrarenal mechanisms in which the unchanged drug together with its glucuronide in urine accounts for only 8.8% of the administered dose.[A7838]
Protein binding Tolfenamic acid presents high protein binding properties reaching 99.7% of the administered dose.[A7838] Studies have studied the changes in protein binding depending on the presence of certain disorders that modify the dialysis equilibrium. These studies verify that modifications in blood creatinine, urea and bilirubin can significantly alter the concentration of unbound tolfenamic acid. The main binding structure is predicted to be related to lipid membrane structures.[A31850]
Half life The estimated half-life of tolfenamic acid is 8.01-13.50 hours.[A31842] When tested intravenously, the reported half-life was 6.1h.[A31849]
Absorption Tolfenamic acid pharmacokinetic is marked by a short tmax of 0.94-2.04 h.[A31842] It also presented a linear pharmacokinetic profile with an AUC from 13-50 mcg/ml.h if administered in a dose of 2-8 mg/kg respectively.[A31843] The oral absorption is delayed and it gives a mean lag-time to absorption of 32 min. The peak plasma concentration of 11.1 mcg/ml.[A31849] The bioavailability of tolfenamic acid is around 75%.[A31851]
Trade names Clotam, Tufnil
Description anthranilic acid derivatives (or fenamate) class of NSAID drugs; COX inhibitor

M

M01AG02 Tolfenamic acid


[M01AG] Fenamates


[M01A] ANTIINFLAMMATORY AND ANTIRHEUMATIC PRODUCTS, NON-STEROIDS


[M01] ANTIINFLAMMATORY AND ANTIRHEUMATIC PRODUCTS


[M] Musculoskeletal system

Toxicity Dose Time Species Model Method Action Positive criterion Reference
TRANSMEMBRANE POTENTIAL 122 24hr rat hepatocytes tetramethylrhodamine ethyl ester (TMRE) decrease AC50 (μM) 40
PROTONOPHORIC UNCOUPLING 278
MEMBRANE POTENTIAL 11.88±0.00 human qHTS-HepG2 MMP assay decrease IC50 163
MEMBRANE POTENTIAL 17.34 human HepG2 MMP assay decrease IC50 163
MEMBRANE POTENTIAL 14.81±4.38 rat hepatocytes MMP assay decrease IC50 163
MEMBRANE POTENTIAL 263.8 µM 30 mins mouse liver mitochondria Rh123 fluorescence (excitation 485 nm, emission 535 nm) are recorded using a fluorescence multi-well plate reader (mCICCP (20 µM) treatments was considered as the 100% baseline for ΔΨm loss) decrease EC20 36
RESPIRATION > 400 µM 60 mins mouse liver mitochondria Oxygen consumption was monitored with 50nM MitoXpress ( an oxygen-sensitive phosphorescent dye) using a spectrofluorimeter (Tecan Infinite 200; λExcitation 380nm; λEmission 650nm). Rotenone (2µM) was used as 100% baseline for complex I inhibition. decrease EC20 36
RESPIRATION 238.7 µM 60 mins mouse liver mitochondria Oxygen consumption was monitored with 50nM MitoXpress ( an oxygen-sensitive phosphorescent dye) using a spectrofluorimeter (Tecan Infinite 200; λExcitation 380nm; λEmission 650nm). Oligomycin A (1µM) was used as 100% baseline for complex II inhibition. increase EC20 36
STATE 2 RESPIRATION 3.4 ± 0.6 rat isolated rat liver mitochondria State 2 respiration ( 96-well plate format using a phosphorescent oxygen-sensitive probe MitoXpress) inhibit UC50 (nmol/mg mitochondrial protein) 40
STATE 3 RESPIRATION 100 nmol/mg mitochondrial protein rat isolated rat liver mitochondria State 3 respiration ( 96-well plate format using a phosphorescent oxygen-sensitive probe MitoXpress) Negative IC50 (nmol/mg mitochondrial protein) 40
LIPID METABOLISM 83.1 24hr rat hepatocytes LipidTox, for neutral lipid accumulation, to evaluate lipid content. accumulation AC50 (μM) 40
GLUTATHIONE METABOLISM 105 24hr rat hepatocytes glutathion depletion: cells were incubated with 50 μM monochlorobimane with 6 μg/ml Hoechst 33342 AC50 (μM) 40
SWELLING > 800 µM 30 mins mouse liver mitochondria swelling assay: Absorbance at 545 nm using a fluorescence multi-well plate reader (CaCl2 (50 µM) was considered as the 100% baseline for the swelling ) increase EC20 36
ROS PRODUCTION NR rat hepatocytes use CM-H2DCFDA to monitor reactive oxygen species Negative AC50 (μM) 40
CYTOCHROME C RELEASE 75 24hr rat hepatocytes cytochrome c release (anti-cytochrome c antibody ) induce AC50 (μM) 40
ER STRESS-INDUCED 50 24hr rat hepatocytes DNA damage 153 induction (GADD153 antibodies) for ER-stress induced apoptosis induce AC50 (μM) 40

Target Dose Time Species Model Method Action Positive criterion Reference
NADH:ubiquinone reductase > 400 µM 60 mins mouse liver mitochondria Oxygen consumption was monitored with 50nM MitoXpress ( an oxygen-sensitive phosphorescent dye) using a spectrofluorimeter (Tecan Infinite 200; λExcitation 380nm; λEmission 650nm). Rotenone (2µM) was used as 100% baseline for complex I inhibition. inhibit EC20 36
Cytochrome c > 400 µM 30 mins mouse liver mitochondria Cytochrome c release was evaluated using ELISA kit ( 20 µg/ml Alamethicin was used as 100% baseline) release EC20 36

Pictogram Signal Statements Precautionary Statement Codes
Danger

Aggregated GHS information provided by 197 companies from 2 notifications to the ECHA C&L Inventory.


H301 (98.48%): Toxic if swallowed [Danger Acute toxicity, oral]


Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.


 P264, P270, P301+P310, P321, P330, P405, and P501; (The corresponding statement to each P-code can be found at the GHS Classification page.)


  • 13710-19-5 2(3-Chloro-2-methylanilino)benzoic acid 2-((3-Chloro-2-methylphenyl)amino)benzoic acid
    2-(3-Chloro-2-methylanilino)benzoic acid 2-(3-Chloro-2-methylanilino)benzoic acid # 2-(3-Chloro-o-toluidino)benzoic Acid
    2-(3-chloro-2-methylphenylamino)benzoic acid 2-([3-Chloro-2-methylphenyl]amino)benzoic acid 2-[(3-Chloro-2-methylphenyl)amino]benzoic Acid
    2-[(3-chloranyl-2-methyl-phenyl)amino]benzoic acid 3G943U18KM A807198
    AB00052244 AB00052244-15 AB00052244_16
    AB00052244_17 AB0032595 AB2000392
    ACMC-209cat AK305709 AKOS012836098
    ANW-20211 API0002084 AS-13748
    Acide tolfenamique Acido tolfenamico Acidum tolfenamicum
    Anthranilic acid, N-(3-chloro-o-tolyl)- BDBM35905 BIDD:GT0343
    BPBio1_000209 BRD-K50133271-001-05-4 BRD-K50133271-001-10-4
    BSPBio_000189 BSPBio_003223 Benzoic acid, 2-((3-chloro-2-methylphenyl)amino)- (9CI)
    Benzoic acid, 2-(3-chloro-2-methylphenylamino)- Benzoic acid, 2-[(3-chloro-2-methylphenyl)amino]- Bifenac
    CAS-13710-19-5 CCG-39189 CHEBI:32243
    CHEMBL121626 CS-2377 Certified Reference Material
    Clotam Clotam (TN) D01183
    DA-11289 DB09216 DSSTox_CID_25409
    DSSTox_GSID_45409 DSSTox_RID_80860 DTXSID1045409
    FT-0652603 GEA 6414 GTPL8769
    HMS1568J11 HMS1921P13 HMS2090D04
    HMS2095J11 HMS2230J13 HMS3370A02
    HMS3651E06 HMS3712J11 HY-B0335
    InChI=1/C14H12ClNO2/c1-9-11(15)6-4-8-12(9)16-13-7-3-2-5-10(13)14(17)18/h2-8,16H,1H3,(H,17,18) J-006962 J10240
    KBio2_001743 KBio2_004311 KBio2_006879
    KBio3_002723 KBioGR_000935 KBioSS_001743
    KS-00000H6I MCULE-9901889833 MLS000028531
    N-(2-Methyl-3-chlorophenyl)anthranilic acid N-(3-Chloro-2-methylphenyl)anthranilic acid N-(3-Chloro-o-tolyl)-anthranilic acid
    NCGC00016705-01 NCGC00016705-02 NCGC00016705-03
    NCGC00016705-04 NCGC00016705-05 NCGC00016705-06
    NCGC00016705-07 NCGC00016705-10 NCGC00022587-03
    NCGC00022587-04 NCGC00022587-05 NSC-757873
    NSC757873 Oprea1_692996 Pharmakon1600-01501198
    Prestwick0_000205 Prestwick1_000205 Prestwick2_000205
    Prestwick3_000205 Prestwick_579 Q59412
    SBB058187 SBI-0051687.P002 SCHEMBL25190
    SEL10850963 SMR000058289 SPBio_001311
    SPBio_002110 SPECTRUM1501198 SR-01000000102
    SR-01000000102-2 SR-01000000102-3 ST51015128
    SW196753-3 Spectrum2_001446 Spectrum3_001762
    Spectrum4_000238 Spectrum5_001143 Spectrum_001263
    TC-108956 Tolfedine Tolfenamic
    Tolfenamic Acid, Pharmaceutical Secondary Standard Tolfenamic acid (JAN/INN) Tolfenamic acid, European Pharmacopoeia (EP) Reference Standard
    Tolfenamic acid, NSAID Tolfenamic acid, VETRANAL(TM), analytical standard Tolfine
    Tox21_110570 Tox21_110570_1 UNII-3G943U18KM
    UNM000001237003 X5948 YEZNLOUZAIOMLT-UHFFFAOYSA-
    YEZNLOUZAIOMLT-UHFFFAOYSA-N ZINC2188 cid_610479
    flufenamic acid analogue, 32 n-(3-chloro-ortho-tolyl)anthranilic acid s1959
    tolfenamic acid tolfenamic-acid

    DrugBank Name Tolfenamic Acid
    DrugBank DB09216
    CAS Number 13710-19-5
    PubChem Compound 610479
    KEGG Drug D01183
    PubChem.Substance 310265123
    ChEBI 32243
    PharmGKB PA166049189
    ChemSpider 530683
    BindingDB 35905.0
    Wikipedia Tolfenamic_acid
    HET TLF
    DPD 928

    1. Chan et al. (2005)