Clofibric Acid

Clofibric acid is a PPARα agonist and hypolipidemic agent.

Biopharmaceutical Characterization and Bioavailability Study of a Tetrazole Analog of Clofibric Acid in Rat.[Pubmed:28216581]

Molecules. 2017 Feb 14;22(2). pii: molecules22020282.

In the current investigation, the physicochemical, biopharmaceutical and pharmacokinetic characterization of a new Clofibric Acid analog (Compound 1) was evaluated. Compound 1 showed affinity by lipophilic phase in 1 to 5 pH interval, indicating that this compound would be absorbed favorably in duodenum or jejunum. Also, Compound 1 possess two ionic species, first above of pH 4.43 and, the second one is present over pH 6.08. The apparent permeability in everted sac rat intestine model was 8.73 x 10(-6) cm/s in duodenum and 1.62 x 10(-5) cm/s in jejunum, suggesting that Compound 1 has low permeability. Elimination constant after an oral administration of 50 mug/kg in Wistar rat was 1.81 h(-1), absorption constant was 3.05 h(-1), Cmax was 3.57 mug/mL at 0.33 h, AUC0-alpha was 956.54 mu/mL.h and distribution volume was 419.4 mL. To IV administration at the same dose, ke was 1.21 h(-1), Vd was 399.6 mL and AUC0-alpha was 747.81 mu/mL.h. No significant differences were observed between pharmacokinetic parameters at every administration route. Bioavailability evaluated was 10.4%. Compound 1 is metabolized to Compound 2 probably by enzymatic hydrolysis, and it showed a half-life of 9.24 h. With these properties, Compound 1 would be considered as a prodrug of Compound 2 with potential as an antidiabetic and anti dyslipidemic agent.

A calix[4]arene derivative and its selective interaction with drugs (clofibric acid, diclofenac and aspirin).[Pubmed:28063965]

Eur J Pharm Sci. 2017 Mar 30;100:1-8.

The synthesis and characterisation of a partially substituted calix[4]arene, namely, 5,11,17,23-tetra-tert-butyl,25,27-bis[aminoethoxy] 26,28-dihydroxycalix[4]arene are reported. Its interaction with commonly used pharmaceuticals (Clofibric Acid, diclofenac and aspirin) was investigated by spectroscopic ((1)H NMR and UV), electrochemical (conductance measurements) and thermal (titration calorimetry) techniques. It is concluded on the basis of the experimental work and molecular simulation studies that the receptor interacts selectively with these drugs. Preliminary studies on the selective extraction of these pharmaceuticals from water by the calix receptor are reported and the potential for a carrier mediated sensor based on this ligand for 'on site' monitoring of pharmaceuticals is discussed.

Assessing the phototransformation of diclofenac, clofibric acid and naproxen in surface waters: Model predictions and comparison with field data.[Pubmed:27657658]

Water Res. 2016 Nov 15;105:383-394.

Phototransformation is important for the fate in surface waters of the pharmaceuticals diclofenac (DIC) and naproxen (NAP) and for Clofibric Acid (CLO), a metabolite of the drug clofibrate. The goal of this paper is to provide an overview of the prevailing photochemical processes, which these compounds undergo in the different conditions found in freshwater environments. The modelled photochemical half-life times of NAP and DIC range from a few days to some months, depending on water conditions (chemistry and depth) and on the season. The model indicates that direct photolysis is the dominant degradation pathway of DIC and NAP in sunlit surface waters, and potentially toxic cyclic amides were detected as intermediates of DIC direct phototransformation. With modelled half-life times in the month-year range, CLO is predicted to be more photostable than DIC or NAP and to be degraded mainly by reaction with the (*)OH radical and with the triplet states of chromophoric dissolved organic matter ((3)CDOM*). The CLO intermediates arising from these processes and detected in this study (hydroquinone and 4-chlorophenol) are, respectively, a chronic toxicant to aquatic organisms and a possible carcinogen for humans. Hydroquinone is formed with only approximately 5% yield upon CLO triplet-sensitised transformation, but it is highly toxic for algae and crustaceans. In contrast, the formation yield of 4-chlorophenol reaches approximately 50% upon triplet sensitisation and approximately 10% by (.)OH reaction. The comparison of model predictions with field data from a previous study yielded a very good agreement in the case of DIC and, when using 4-carboxybenzophenone as proxy for triplet sensitisation by CDOM, a good agreement was found for CLO as well. In the case of NAP, the comparison with field data suggests that its direct photolysis quantum yield approaches or even falls below the lower range of literature values.

Photocatalytic degradation of clofibric acid by g-C3N4/P25 composites under simulated sunlight irradiation: The significant effects of reactive species.[Pubmed:28068571]

Chemosphere. 2017 Apr;172:193-200.

Pharmaceutically emerging micropollutants have become an environmental concern in recent years. In the present paper, the reactive species (RSs)-induced degradation mechanism of Clofibric Acid (CA) was investigated using a newly sunlight-driven g-C3N4/P25 photocatalyst. A very low g-C3N4 content of 8.0 weight percent resulted in a 3.36 and a 2.29 times faster reaction rate for CA photodegradation than for pristine g-C3N4 and P25, respectively. Electron spin resonance and quenching experiments demonstrated the participation of HO, h(+), e(-), (1)O2 and O2(.-) in the photocatalytic system, and the contribution rates were calculated to 73.3%, 15.3%, 5.1%, 6.7% and 33.1%, respectively. According to the pulse radiolysis measurements and the competitive kinetics approaches, the bimolecular reaction rate constants for HO, e(-), and (1)O2 with CA were (8.47 +/- 0.33) x 10(9) M(-1)s(-1), (6.41 +/- 0.48) x 10(9) M(-1)s(-1) and (6.6 +/- 0.37) x 10(6) M(-1)s(-1), respectively. RSs were found to significantly influence the degradation of CA, and the degradation pathways occurred primarily via e(-) reduction, HO addition and (1)O2 attack reactions on the basis of mass spectrometry and theoretical calculations.

Peroxisome proliferator-activated receptors in the cardiovascular system.[Pubmed:10696077]

Br J Pharmacol. 2000 Mar;129(5):823-34.

Peroxisome proliferator-activated receptor (PPAR)s are a family of three nuclear hormone receptors, PPARalpha, -delta, and -gamma, which are members of the steriod receptor superfamily. The first member of the family (PPARalpha) was originally discovered as the mediator by which a number of xenobiotic drugs cause peroxisome proliferation in the liver. Defined functions for all these receptors, until recently, mainly concerned their ability to regulate energy balance, with PPARalpha being involved in beta-oxidation pathways, and PPARgamma in the differentiation of adipocytes. Little is known about the functions of PPARdelta, though it is the most ubiquitously expressed. Since their discovery, PPARs have been shown to be expressed in monocytes/macrophages, the heart, vascular smooth muscle cells, endothelial cells, and in atherosclerotic lesions. Furthermore, PPARs can be activated by a vast number of compounds including synthetic drugs, of the clofibrate, and anti-diabetic thiazoldinedione classes, polyunsaturated fatty acids, and a number of eicosanoids, including prostaglandins, lipoxygenase products, and oxidized low density lipoprotein. This review will aim to introduce the field of PPAR nuclear hormone receptors, and discuss the discovery and actions of PPARs in the cardiovascular system, as well as the source of potential ligands.

Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta.[Pubmed:9113986]

Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4312-7.

Fatty acids (FAs) and their derivatives are essential cellular metabolites whose concentrations must be closely regulated. This implies that regulatory circuits exist which can sense changes in FA levels. Indeed, the peroxisome proliferator-activated receptor alpha (PPARalpha) regulates lipid homeostasis and is transcriptionally activated by a variety of lipid-like compounds. It remains unclear as to how these structurally diverse compounds can activate a single receptor. We have developed a novel conformation-based assay that screens activators for their ability to bind to PPARalpha/delta and induce DNA binding. We show here that specific FAs, eicosanoids, and hypolipidemic drugs are ligands for PPARalpha or PPARdelta. Because altered FA levels are associated with obesity, atherosclerosis, hypertension, and diabetes, PPARs may serve as molecular sensors that are central to the development and treatment of these metabolic disorders.

Mechanism of action of fibrates.[Pubmed:8497455]

Postgrad Med J. 1993;69 Suppl 1:S34-41.

Fibrates are effective in hypertriglyceridaemia and hypercholesterolaemia. They affect both triglyceride-rich and cholesterol-rich particles and have at least four separate modes of action. These include limitation of substrate availability for triglyceride synthesis in the liver; promotion of the action of lipoprotein lipase; modulation of low density lipoprotein (LDL) receptor/ligand interaction and stimulation of reverse cholesterol transport. Studies of LDL metabolism suggest the existence of two separate catabolic pathways involving the LDL receptor and scavenger mechanism(s). The former route is anti-atherogenic; the latter pro-atherogenic. At low triglyceride levels, the fractional clearance of LDL by the receptor is high. The action of fibrates is to promote the secretion of LDL which is cleared by a receptor-mediated mechanism. Catabolism of this fraction increases from 40% of the plasma pool per day in untreated to 60% per day in treated subjects. By activating lipoprotein lipase, fibrates also reduce the amount of small dense LDL, the fraction which is most likely to generate peroxidation products. Hence, fibrates stimulate LDL receptor-dependent clearance mechanisms and reduce the amount of LDL available for oxidation.