PYRIDOXINE CLOFIBRATE

US Previously Marketed

Details

Stereochemistry	ACHIRAL
Molecular Formula	C10H11ClO3.C8H11NO3
Molecular Weight	383.823
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=C(O)C(CO)=C(CO)C=N1.CC(C)(OC2=CC=C(Cl)C=C2)C(O)=O

InChI

InChIKey=XHNQLDLSWAXHBW-UHFFFAOYSA-N

InChI=1S/C10H11ClO3.C8H11NO3/c1-10(2,9(12)13)14-8-5-3-7(11)4-6-8;1-5-8(12)7(4-11)6(3-10)2-9-5/h3-6H,1-2H3,(H,12,13);2,10-12H,3-4H2,1H3

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/7853724 | https://www.ncbi.nlm.nih.gov/pubmed/27354598

Clofibrate is a fibric acid derivative used to lower cholesterol and triglyceride (fat-like substances) levels in the blood. This may help prevent medical problems caused by such substances clogging the blood vessels. However, this treatment was discontinued in 2002 due to adverse effects. Clofibrate is an agonist of the PPAR-α receptor in muscle, liver, and other tissues. This agonism ultimately leads to modification in gene expression resulting in increased beta-oxidation, decreased triglyceride secretion, increased HDL, and increased lipoprotein lipase activity. Clofibrate increased the activity of extrahepatic lipoprotein lipase (LL), thereby increasing lipoprotein triglyceride lipolysis, inhibited the synthesis, and increases the clearance of apolipoprotein B, a carrier molecule for VLDL. In addition, clofibrate was investigated as a novel therapy agent in multiple myeloma and it shown the promising results.

Approval Year

Targets

Primary Target	Pharmacology	Potency
Peroxisome proliferator-activated receptor alpha 62 Target ID: CHEMBL239 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19817384	Agonist 2678	50.0 µM [EC50]
Taste receptor type 1 member 3 14 Target ID: Q7RTX0 Gene ID: 83756.0 Gene Symbol: TAS1R3 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/19817384	Inhibitor 8297	28.0 µM [IC50]
Peroxisome proliferator-activated receptor alpha 62 Target ID: CHEMBL239 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10922459	Agonist 2678

Conditions

Condition	Modality	Targets	Highest Phase	Product
Hyperlipoproteinemia 9 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7853724	Primary		Approved 8429	ATROMID-S Approved Use Unknown Launch Date 1967
Multiple myeloma 159 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27354598	Primary		Basic research	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
216 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7550835/	100 mg/kg single, oral dose: 100 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		CLOFIBRIC ACID plasma	Homo sapiens population: UNHEALTHY age: NEWBORN sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
30649 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7550835/	100 mg/kg single, oral dose: 100 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		CLOFIBRIC ACID plasma	Homo sapiens population: UNHEALTHY age: NEWBORN sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
103.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7550835/	100 mg/kg single, oral dose: 100 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		CLOFIBRIC ACID plasma	Homo sapiens population: UNHEALTHY age: NEWBORN sex: FEMALE / MALE food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OATP1B1 788 MRP2 383 P-gp 1461		CYP4A1 17 CYP2B1 26 UGT 29

Drug as perpetrator

Target	Modality	Activity
OATP1B1 803	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/16316932/ Page: 6.0	moderate [Inhibition 100 uM]
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/16316932/	no
MRP2 475	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/16316932/	not significant
CYP2B1 41	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/7685601/	yes
CYP4A1 25	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/7685601/	yes
UGT 59	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/11033061/	yes

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:34648	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:34648
ChemicalBook	CB1282957	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB1282957
MolPort	MolPort-000-146-057	https://www.molport.com/shop/molecule-link/MolPort-000-146-057
ZINC	ZINC000000001187	http://zinc15.docking.org/substances/ZINC000000001187
eMolecules	487665	https://www.emolecules.com/cgi-bin/more?vid=487665

PubMed

Title	Date	PubMed
Effect of halofenate and clofibrate on lipid synthesis in rat adipocytes.	1975 Feb 20	1120140
The slow induction of resistant hepatocytes during initiation of hepatocarcinogenesis by the nongenotoxic carcinogen clofibrate.	1999 Dec	10600397
Activators of peroxisome proliferator-activated receptor-alpha induce the expression of the uncoupling protein-3 gene in skeletal muscle: a potential mechanism for the lipid intake-dependent activation of uncoupling protein-3 gene expression at birth.	1999 Jun	10342807
Mitochondrial damage by the "pro-oxidant" peroxisomal proliferator clofibrate.	1999 Nov	10569642
[A 50-year history of new drugs in Japan: the developments and trends of antihyperlipidemic drugs].	2001	11968219
Use of isotopes and LC-MS-ESI-TOF for mechanistic studies of tienilic acid metabolic activation.	2001	11764926
Neonatal mouse model: review of methods and results.	2001	11695548
Effect of bezafibrate and clofibrate on the heme-iron geometry of ferrous nitrosylated heme-human serum albumin: an EPR study.	2001 Apr	11374593
WY-14,643 and other agonists of the peroxisome proliferator-activated receptor reveal a new mode of action for salicylic acid in soybean disease resistance.	2001 Apr	11346966
Cytochrome P450 1A1 and 4A activities in isolated rat spleen lymphocytes.	2001 Apr	11338675
Stimulatory effect of clofibrate on the action of estradiol in the mammary gland but not in the uterus of rats.	2001 Apr	11259527
Characterization of clofibrate-induced retrograde Golgi membrane movement to the endoplasmic reticulum: clofibrate distinguishes the Golgi from the trans Golgi network.	2001 Aug	11577722
Detection of DNA adducts using a quantitative long PCR technique and the fluorogenic 5' nuclease assay (TaqMan).	2001 Dec 12	11733068
The transcription of the peroxisome proliferator-activated receptor alpha gene is regulated by protein kinase C.	2001 Dec 15	11701232
Major clofibrate effects on liver and plasma lipids are independent of changes in polyunsaturated fatty acid composition induced by dietary fat.	2001 Feb	11269691
Molecular cloning and regulation of expression of two novel mouse CYP4F genes: expression in peroxisome proliferator-activated receptor alpha-deficient mice upon lipopolysaccharide and clofibrate challenges.	2001 Feb	11160642
Stimulatory effect of clofibrate and gemfibrozil administration on the formation of fatty acid esters of estradiol by rat liver microsomes.	2001 Jan	11123380
Effects of polyunsaturated fatty acids and clofibrate on chicken stearoyl-coA desaturase 1 gene expression.	2001 Jan 12	11162472
Hormonal regulation of multiple promoters of the rat mitochondrial glycerol-3-phosphate dehydrogenase gene: identification of a complex hormone-response element in the ubiquitous promoter B.	2001 Jul	11454004
Peroxisome proliferator-activated receptors (PPARs): novel therapeutic targets in renal disease.	2001 Jul	11422732
The biochemistry of hypo- and hyperlipidemic fatty acid derivatives: metabolism and metabolic effects.	2001 Jul	11412891
Expression and characterization of recombinant rat Acyl-CoA synthetases 1, 4, and 5. Selective inhibition by triacsin C and thiazolidinediones.	2001 Jul 6	11319222
Localization of mRNAs encoding peroxisomal proteins in cell culture by non-radioactive in situ hybridization. Comparison of rat and human hepatoma cells and their responses to two divergent hypolipidemic drugs.	2001 Jun	11455450
Accumulation of medium chain acyl-CoAs during beta-oxidation of long chain fatty acid by isolated peroxisomes from rat liver.	2001 Jun	11411544
Combined interferon-alfa, 13-cis-retinoic acid, and alpha-tocopherol in locally advanced head and neck squamous cell carcinoma: novel bioadjuvant phase II trial.	2001 Jun 15	11408495
Allosteric modification of oxygen delivery by hemoglobin.	2001 Mar	11226087
The expression of PPAR-associated genes is modulated through postnatal development of PPAR subtypes in the small intestine.	2001 Mar 30	11278173
Peroxisome-proliferator-activated receptors as physiological sensors of fatty acid metabolism: molecular regulation in peroxisomes.	2001 May	11356172
Autoantibodies to lipids in bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome.	2001 Oct	11588459
Comparison of various characteristics of women who do and do not attend for breast cancer screening.	2002	11879559
Effects of fatty acids on mitochondrial beta-oxidation enzyme gene expression in renal cell lines.	2002 Aug	12110517
Eighth World Congress of Intensive and Critical Care Medicine, 28 October-1 November 2001, Sydney, Australia: Harm minimization and effective risk management.	2002 Feb	11940273
Do lipid-lowering drugs cause erectile dysfunction? A systematic review.	2002 Feb	11818357
Synergistic effect of 4-hydroxynonenal and PPAR ligands in controlling human leukemic cell growth and differentiation.	2002 Feb 1	11827749
In vitro induction of bilirubin conjugation in primary rat hepatocyte culture.	2002 Feb 15	11829457
Peroxisome proliferator-activated receptor ligands as antiatherogenic agents: panacea or another Pandora's box?	2002 Jan	12000972
Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFkappaB.	2002 Jan 11	11779144
Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size.	2002 Jul	12087064
PPARgamma ligands suppress proliferation of human urothelial basal cells in vitro.	2002 Jun	12012326
Effects of peroxisome proliferator-activated receptor agonists on LPS-induced neuronal death in mixed cortical neurons: associated with iNOS and COX-2.	2002 Jun 21	12031542
Potentiation of TNF-alpha-stimulated group IIA phospholipase A(2) expression by peroxisome proliferator-activated receptor alpha activators in rat mesangial cells.	2002 Mar	11856764
Effect of clofibrate administration on the esterification and deesterification of steroid hormones by liver and extrahepatic tissues in rats.	2002 Mar 1	11911851
Getting a GRIP on liprins.	2002 Mar 28	11931733
Blunted induction of hepatic CYP4A in TNF (p55-/-/p75-/-) double receptor knockout mice following clofibrate treatment.	2002 May	12069177

Patents

Sample Use Guides

In Vivo Use Guide

For oral dosage form (capsules): for high cholesterol: adults—1.5 to 2 grams a day. This is divided into two to four doses. Children—Dose must be determined by doctor.

Route of Administration: Oral

In Vitro Use Guide

The antitumor apoptotic effect of clofibrate at doses ranging from 0.1-600 μM was investigated on four human and one murine myeloma cell lines, as well as in two human lymphoma cell lines, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide assay. Clofibrate significantly reduced cell viability in all tested myeloma and lymphoma cell lines in a dose-dependent manner, while healthy cells were hardly affected.

Name

Type

Language

PYRIDOXINE CLOFIBRATE

Common Name

English

CLOFIBRIC ACID PYRIDOXINE SALT

Common Name

English

CLOFIBRIC ACID PYRIDOXINE SALT [MI]

Common Name

English

PROPANOIC ACID, 2-(4-CHLOROPHENOXY)-2-METHYL-, COMPD. WITH 5-HYDROXY-6-METHYL-3,4-PYRIDINEDIMETHANOL (1:1)

Common Name

English

Code System Code Type Description

MERCK INDEX

m3641