T3DB: Gemfibrozil

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (2)XML

Targets (2)

Record Information

Version

2.0

Creation Date

2014-09-11 05:17:33 UTC

Update Date

2014-12-24 20:26:57 UTC

Accession Number

T3D4809

Identification

Common Name

Gemfibrozil

Class

Small Molecule

Description

A 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

MOL SDF PDB SMILES InChI

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 Formula

C₁₅H₂₂O₃

Average Molecular Mass

250.333 g/mol

Monoisotopic Mass

250.157 g/mol

CAS Registry Number

25812-30-0

IUPAC Name

5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid

Traditional Name

gemfibrozil

SMILES

CC1=CC(OCCCC(C)(C)C(O)=O)=C(C)C=C1

InChI Identifier

InChI=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 Key

InChIKey=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.

Kingdom

Organic compounds

Super Class

Benzenoids

Class

Phenol ethers

Sub Class

Not Available

Direct Parent

Phenol 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 Framework

Aromatic homomonocyclic compounds

External Descriptors

aromatic ether (CHEBI:5296 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Cytoplasm
Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

Not Available

Biological Roles

Not Available

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	62°C
Boiling Point	158.5°C at 2.00E-02 mm Hg
Solubility	10 mg/mL (in base)
LogP	3.4

Predicted Properties

Property	Value	Source
Water Solubility	0.028 g/L	ALOGPS
logP	3.61	ALOGPS
logP	4.39	ChemAxon
logS	-4	ALOGPS
pKa (Strongest Acidic)	4.42	ChemAxon
pKa (Strongest Basic)	-4.8	ChemAxon
Physiological Charge	-1	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	46.53 Å²	ChemAxon
Rotatable Bond Count	6	ChemAxon
Refractivity	71.82 m³·mol⁻¹	ChemAxon
Polarizability	28.9 Å³	ChemAxon
Number of Rings	1	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-0076-6950000000-ea8e6e101df62d80313a	2017-09-01	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positive	splash10-05g0-9721000000-e7c61af259566e389d95	2017-10-06	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , negative	splash10-00di-0900000000-24b892a8bd68bdf9cef6	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , negative	splash10-00di-0900000000-7a9eaaae65f0e1efcbc4	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , negative	splash10-00di-0900000000-12b36ea4be2a1b876c61	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , negative	splash10-00di-0900000000-647692900acca2ec2441	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , negative	splash10-00di-0900000000-41c8e4e08162dfaf1fc4	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , negative	splash10-00di-0900000000-28d25da91cc1d391cc84	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , negative	splash10-00di-0900000000-a08267bdc97edb1a2601	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , negative	splash10-00di-0900000000-a133a90a69b988c45ffb	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-0059-6910000000-0ad597adcb83e9f4e4ba	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-0059-8900000000-8684ba342d3eb0a7f602	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-05cr-9400000000-008385b887cc6ac6d748	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-0ac0-9300000000-74e1b5c007dd49af6a01	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-0ab9-9200000000-cc36aaee7c70d8e92f96	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QFT , positive	splash10-0a4i-9100000000-ce28ed926945c33079d6	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 90V, Negative	splash10-052g-9400000000-7df8d3b3c3d528585b24	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 75V, Positive	splash10-0ab9-9200000000-a29f6ecb2573b0a72463	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 90V, Positive	splash10-0a4i-9100000000-ce28ed926945c33079d6	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Positive	splash10-004i-0970000000-b6b747ddc80c5e277857	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 30V, Negative	splash10-0002-0390000000-b42eee5672459e8cc06b	2021-09-20	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0zfr-0290000000-ed946d5de4de22b6bf20	2016-08-01	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0a59-4970000000-01a0d2adb215feef78cc	2016-08-01	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-053r-9500000000-f971c24cd2f474fea5a3	2016-08-01	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0002-0490000000-2ba2ea9e2ef949ad859b	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-00di-1950000000-865193b239a02078f9b6	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-00di-4900000000-adb1ff2509f9361f33fe	2016-08-03	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 400 MHz, CDCl₃, experimental)	Not Available	2014-09-20	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 100.40 MHz, CDCl₃, experimental)	Not Available	2014-09-23	View Spectrum

Toxicity Profile

Route of Exposure

Well absorbed from gastrointestinal tract (within 1-2 hours).

Mechanism of Toxicity

Gemfibrozil 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.

Metabolism

Hepatic. 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 Values

Oral, mouse: LD₅₀ = 3162 mg/kg.

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

3, not classifiable as to its carcinogenicity to humans. (1)

Uses/Sources

For 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 Level

Not Available

Health Effects

Not Available

Symptoms

Symptoms of overdose include abdominal cramps, diarrhea, joint and muscle pain, nausea, and vomiting.

Treatment

Not Available

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

HMDB ID

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

UniProt ID

Not Available

OMIM ID

ChEBI ID

5296

BioCyc ID

Not Available

CTD ID

D015248

Stitch ID

Not Available

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

Gemfibrozil

References

Synthesis Reference

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

MSDS

Link

General References

International Agency for Research on Cancer (2014). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. [Link]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Targets

Target Details

1. Peroxisome proliferator-activated receptor alpha

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

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 ]
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 ]
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 ]
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 ]
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 ]
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 ]

Target Details

2. Peroxisome proliferator-activated receptor gamma

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

Type	Value	Assay Type	Assay Source
AC50	8.69 uM	NVS_NR_hPPARg	Novascreen

References

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 ]

Gemfibrozil (T3D4809)

Structure for T3D4809: Gemfibrozil

Targets

References

Binding/Activity Constants

References