Disease relevance of Clofop

• This increase in plasma apo A-II was due to a direct effect on hepatic apo A-II production, since fenofibric acid induced apo A-II mRNA levels to 450 and 250% of control levels in primary cultures of human hepatocytes and in human hepatoblastoma HepG2 cells respectively [1].
• In HuH7 human hepatoma cells, the PON-1 secreted enzymatic activity and mRNA levels were increased by fenofibric acid (approximately 70%) and decreased by several statins (approximately 50%) [2].
• A comparative in vitro phototoxicity study has been carried out on the anti-hyperlipoproteinemic drug fenofibrate, its metabolites and the photoproducts of fenofibric acid [3].
• The photosensitization of DNA damage by KP and fenofibric acid (FB), the main metabolite of fenofibrate, and their parent compound, benzophenone (BZ), was examined on a 32P-end-labeled synthetic oligonucleotide in phosphate-buffered solution using gel sequencing experiments [4].
• Although the serum concentrations of fenofibric acid were 1.3-fold higher in women than in men, which was probably due to the higher body weight in men (1.2-fold), this difference can hardly explain the favorable effect on lipoproteins in women [5].

High impact information on Clofop

• Treatment of human primary hepatocytes with fenofibric acid (500 microM) provoked an 83 and 50% increase in apo A-I secretion and mRNA levels, respectively, supporting that a direct action of fibrates on liver human apo A-I production leads to the observed increase in plasma apo A4 and HDL-cholesterol [6].
• PPARalpha activity was assessed by quantification of the key gene target carnitine palmitoyl acyl-CoA transferase 1 (CPT1A) messenger RNA (mRNA).The influence of HCV core protein on PPARalpha mRNA expression was analyzed in vitro by real-time PCR in HCV core-expressing HepG2 cells activated with the PPARalpha ligand fenofibric acid [7].
• In the hepatocyte cell line AML-12, fenofibric acid, but not BRL 49653, induced LPL mRNA, whereas in 3T3-L1 preadipocytes, the PPARgamma ligand induced LPL mRNA levels much quicker and to a higher extent than fenofibric acid [8].
• We also show that the intervention of fenofibric acid in cellular lipid metabolism directly affects the expression pattern of HCV core protein [9].
• Incubation of human hepatocytes or hepatoblastoma HepG2 and Huh7 cells with synthetic PPAR alpha agonists, fenofibric acid, or Wy 14643 resulted in an increase of UGT2B4 mRNA levels [10].

Chemical compound and disease context of Clofop

• Relationship between plasma fenofibric acid levels and the effect of micronized fenofibrate on cholesterol, low-density-lipoprotein cholesterol and apolipoprotein B in patients with primary hypercholesterolemia [11].

Biological context of Clofop

• Incubation of fenofibrate in whole blood caused hydrolysis of the ester bond with the release of fenofibric acid [12].
• Lack of a genetic polymorphism in the glucuronidation of fenofibric acid [13].
• Nuclear run-on experiments demonstrated that fenofibric acid and alpha-bromopalmitate decreased apo A-I and increased acyl-CoA oxidase gene expression at the transcriptional level [14].
• Also, fenofibric acid steady-state pharmacokinetics were evaluated with and without simvastatin [15].
• The increase of the apoA-IV mRNA level could be correlated with a clear enhancement of DNase I hypersensitive sites in the 5' flanking region of the gene in nuclei of HepG2 cells treated with fenofibric acid [16].

Anatomical context of Clofop

• In primary cultures of rat and human hepatocytes, fenofibric acid lowered apo C-III mRNA in a time- and dose-dependent manner [17].
• Platelet derived growth factor (PDGF) is considered to be an important growth promoting agent for vascular smooth muscle cells (VSMC) and fenofibric acid (a hypolipidaemic drug) has been reported to be a PDGF antagonist [18].
• The principal compound in feces was unchanged fenofibrate, together with smaller quantities of fenofibric acid and polar unknown metabolite(s) [19].
• To investigate this issue, we have irradiated human skin cells (keratinocytes and fibroblasts) in the presence of fenofibric acid (the active phototoxic metabolite of fenofibrate) [20].
• Dilazep and fenofibric acid inhibit MCP-1 mRNA expression in glycoxidized LDL-stimulated human endothelial cells [21].

Associations of Clofop with other chemical compounds

• Here we show that fenofibrate ester, but not fenofibric acid, functions as an LXR antagonist by directly binding to LXRs [22].
• In addition, apolipoprotein CIII mRNA was decreased by both fenofibric acid and compound 1 in rat hepatocytes [23].
• Significant increases (3- to 6-fold) in amodiaquine N-deethylase (a functional probe for CYP2C8 activity) also were observed with clofibric acid, fenofibric acid, and rifampin, in agreement with the mRNA finding [24].
• Both 10 microg/ml dilazep and 100 microM fenofibric acid abrogated MCP-1 mRNA expression [21].
• Coadministration of multiple doses of fenofibrate and ezetimibe produced no statistically significant effect on the pharmacokinetics of fenofibric acid but significantly increased exposures to total ezetimibe and ezetimibe glucuronide (P < 0.05) [25].

Gene context of Clofop

• CONCLUSIONS: In human hepatocytes, both fenofibric acid and clofibric acid are inducers of CYP3A4 and CYP2C8 [24].
• METHODS: Effects of gemfibrozil, fenofibric acid, and clofibric acid on expression levels of cytochromes P450 (CYPs) 3A4 and 2C8 and UDP-glucuronyltransferase (UGT) 1A1 were evaluated in primary human hepatocyte cultures [24].
• Fenofibric acid, an agonist ligand for the peroxisome proliferator-activated receptor-alpha, inhibited basal and bFGF-stimulated PAI-1 expression [26].
• Fenofibric acid concomitantly induced LAH activity and peroxisomal PCOA in rat hepatocytes [27].
• CONCLUSIONS: Fenofibric acid increased transcription of ABCA1 gene in a liver X receptor-dependent manner [28].

Analytical, diagnostic and therapeutic context of Clofop

• Plasma fenofibric acid concentrations were measured by high-performance liquid chromatography, and pharmacokinetic parameters were calculated [29].
• Fenofibrate and fenofibric acid analysis by capillary electrophoresis [12].
• The concentration of the pharmacologically active compound, fenofibric acid, was determined by means of HPLC with UV detection [30].
• Hemodialysis did not modify the plasma levels and the ultrafiltrates contained very small amounts of fenofibric acid [31].

References