Tmic
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Record Information
Version2.0
Creation Date2014-09-11 05:17:33 UTC
Update Date2014-12-24 20:26:57 UTC
Accession NumberT3D4809
Identification
Common NameGemfibrozil
ClassSmall Molecule
DescriptionA lipid-regulating agent that lowers elevated serum lipids primarily by decreasing serum triglycerides with a variable reduction in total cholesterol. These decreases occur primarily in the VLDL fraction and less frequently in the LDL fraction. Gemfibrozil increases HDL subfractions HDL2 and HDL3 as well as apolipoproteins A-I and A-II. Its mechanism of action has not been definitely established.
Compound Type
  • Drug
  • Ether
  • Hypolipidemic Agent
  • Metabolite
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
2,2-Dimethyl-5-(2,5-dimethylphenoxy)valeriansaeure
2,2-Dimethyl-5-(2,5-xylyloxy)valeriansaeure
2,2-Dimethyl-5-(2,5-xylyloxy)valeric acid
Gemfibrozilo
Gemfibrozilum
Gemlipid
Gen-Fibro
Genlip
Jezil
Lipur
Lopid
Chemical FormulaC15H22O3
Average Molecular Mass250.333 g/mol
Monoisotopic Mass250.157 g/mol
CAS Registry Number25812-30-0
IUPAC Name5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid
Traditional Namegemfibrozil
SMILESCC1=CC(OCCCC(C)(C)C(O)=O)=C(C)C=C1
InChI IdentifierInChI=1S/C15H22O3/c1-11-6-7-12(2)13(10-11)18-9-5-8-15(3,4)14(16)17/h6-7,10H,5,8-9H2,1-4H3,(H,16,17)
InChI KeyInChIKey=HEMJJKBWTPKOJG-UHFFFAOYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as phenol ethers. These are aromatic compounds containing an ether group substituted with a benzene ring.
KingdomOrganic compounds
Super ClassBenzenoids
ClassPhenol ethers
Sub ClassNot Available
Direct ParentPhenol ethers
Alternative Parents
Substituents
  • Phenoxy compound
  • P-xylene
  • Xylene
  • Phenol ether
  • Alkyl aryl ether
  • Monocyclic benzene moiety
  • Carboxylic acid derivative
  • Carboxylic acid
  • Ether
  • Monocarboxylic acid or derivatives
  • Organic oxygen compound
  • Organic oxide
  • Carbonyl group
  • Organooxygen compound
  • Hydrocarbon derivative
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point62°C
Boiling Point158.5°C at 2.00E-02 mm Hg
Solubility10 mg/mL (in base)
LogP3.4
Predicted Properties
PropertyValueSource
Water Solubility0.028 g/LALOGPS
logP3.61ALOGPS
logP4.39ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)4.42ChemAxon
pKa (Strongest Basic)-4.8ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area46.53 ŲChemAxon
Rotatable Bond Count6ChemAxon
Refractivity71.82 m³·mol⁻¹ChemAxon
Polarizability28.9 ųChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0076-6950000000-ea8e6e101df62d80313aView in MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positivesplash10-05g0-9721000000-e7c61af259566e389d95View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-00di-0900000000-24b892a8bd68bdf9cef6View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-00di-0900000000-7a9eaaae65f0e1efcbc4View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-00di-0900000000-12b36ea4be2a1b876c61View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-00di-0900000000-647692900acca2ec2441View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-00di-0900000000-41c8e4e08162dfaf1fc4View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , negativesplash10-00di-0900000000-28d25da91cc1d391cc84View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , negativesplash10-00di-0900000000-a08267bdc97edb1a2601View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-ITFT , negativesplash10-00di-0900000000-a133a90a69b988c45ffbView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0059-6910000000-0ad597adcb83e9f4e4baView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0059-8900000000-8684ba342d3eb0a7f602View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-05cr-9400000000-008385b887cc6ac6d748View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0ac0-9300000000-74e1b5c007dd49af6a01View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0ab9-9200000000-cc36aaee7c70d8e92f96View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-QFT , positivesplash10-0a4i-9100000000-ce28ed926945c33079d6View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0zfr-0290000000-ed946d5de4de22b6bf20View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0a59-4970000000-01a0d2adb215feef78ccView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-053r-9500000000-f971c24cd2f474fea5a3View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0002-0490000000-2ba2ea9e2ef949ad859bView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-00di-1950000000-865193b239a02078f9b6View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-00di-4900000000-adb1ff2509f9361f33feView in MoNA
1D NMR1H NMR SpectrumNot AvailableView in JSpectraViewer
1D NMR13C NMR SpectrumNot AvailableView in JSpectraViewer
Toxicity Profile
Route of ExposureWell absorbed from gastrointestinal tract (within 1-2 hours).
Mechanism of ToxicityGemfibrozil increases the activity of extrahepatic lipoprotein lipase (LL), thereby increasing lipoprotein triglyceride lipolysis. It does so by activating Peroxisome proliferator-activated receptor-alpha (PPAR‘±) 'transcription factor ligand', a receptor that is involved in metabolism of carbohydrates and fats, as well as adipose tissue differentiation. This increase in the synthesis of lipoprotein lipase thereby increases the clearance of triglycerides. Chylomicrons are degraded, VLDLs are converted to LDLs, and LDLs are converted to HDL. This is accompanied by a slight increase in secretion of lipids into the bile and ultimately the intestine. Gemfibrozil also inhibits the synthesis and increases the clearance of apolipoprotein B, a carrier molecule for VLDL.
MetabolismHepatic. Gemfibrozil mainly undergoes oxidation of a ring methyl group to successively form a hydroxymethyl and a carboxyl metabolite. Route of Elimination: Approximately seventy percent of the administered human dose is excreted in the urine, mostly as the glucuronide conjugate, with less than 2% excreted as unchanged gemfibrozil. Half Life: 1.5 hours
Toxicity ValuesOral, mouse: LD50 = 3162 mg/kg.
Lethal DoseNot Available
Carcinogenicity (IARC Classification)3, not classifiable as to its carcinogenicity to humans. (1)
Uses/SourcesFor treatment of adult patients with very high elevations of serum triglyceride levels (types IV and V hyperlipidemia) who are at risk of developing pancreatitis (inflammation of the pancreas) and who do not respond adequately to a strict diet.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsSymptoms of overdose include abdominal cramps, diarrhea, joint and muscle pain, nausea, and vomiting.
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01241
HMDB IDHMDB15371
PubChem Compound ID3463
ChEMBL IDCHEMBL457
ChemSpider ID3345
KEGG IDC07020
UniProt IDNot Available
OMIM ID
ChEBI ID5296
BioCyc IDNot Available
CTD IDD015248
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkGemfibrozil
References
Synthesis Reference

Gianfranco Piccoli, Antonio Tarquini, Giovanni Frare, “Process for the preparation of gemfibrozil.” U.S. Patent US5654476, issued May, 1980.

MSDSLink
General References
  1. International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Zinc ion binding
Specific Function:
Ligand-activated transcription factor. Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety. Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2. May be required for the propagation of clock information to metabolic pathways regulated by PER2.
Gene Name:
PPARA
Uniprot ID:
Q07869
Molecular Weight:
52224.595 Da
References
  1. Clavey V, Copin C, Mariotte MC, Bauge E, Chinetti G, Fruchart J, Fruchart JC, Dallongeville J, Staels B: Cell culture conditions determine apolipoprotein CIII secretion and regulation by fibrates in human hepatoma HepG2 cells. Cell Physiol Biochem. 1999;9(3):139-49. [10494028 ]
  2. Bosse Y, Pascot A, Dumont M, Brochu M, Prud'homme D, Bergeron J, Despres JP, Vohl MC: Influences of the PPAR alpha-L162V polymorphism on plasma HDL(2)-cholesterol response of abdominally obese men treated with gemfibrozil. Genet Med. 2002 Jul-Aug;4(4):311-5. [12172398 ]
  3. Pahan K, Jana M, Liu X, Taylor BS, Wood C, Fischer SM: Gemfibrozil, a lipid-lowering drug, inhibits the induction of nitric-oxide synthase in human astrocytes. J Biol Chem. 2002 Nov 29;277(48):45984-91. Epub 2002 Sep 18. [12244038 ]
  4. Shoji Y, Sanekata A, Sato M, Imaizumi K: Preparation of antiserum against rat delta6-desaturase and its use to evaluate the desaturase protein levels in rats treated with gemfibrozil, a ligand for peroxisome proliferator-activated receptor alpha. Biosci Biotechnol Biochem. 2003 May;67(5):1177-8. [12834305 ]
  5. Rizvi F, Iftikhar M, George JP: Beneficial effects of fish liver preparations of sea bass (Lates calcarifer) versus gemfibrozil in high fat diet-induced lipid-intolerant rats. J Med Food. 2003 Summer;6(2):123-8. [12935323 ]
  6. Cunningham ML, Collins BJ, Hejtmancik MR, Herbert RA, Travlos GS, Vallant MK, Stout MD: Effects of the PPARalpha Agonist and Widely Used Antihyperlipidemic Drug Gemfibrozil on Hepatic Toxicity and Lipid Metabolism. PPAR Res. 2010;2010. pii: 681963. doi: 10.1155/2010/681963. Epub 2010 Oct 4. [20953357 ]
General Function:
Zinc ion binding
Specific Function:
Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels (By similarity).
Gene Name:
PPARG
Uniprot ID:
P37231
Molecular Weight:
57619.58 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
AC508.69 uMNVS_NR_hPPARgNovascreen
References
  1. Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]