Fenofibrate inhibits CYP2B6 (IC50=0.7±0.2 μM) and CYP2C19 (IC50=0.2±0.1 μM) with a fair degree of potency. According to reference [1], fenofibrate exhibits moderate inhibitory effects on CYP2C8 (IC50=4.8±1.7 μM) and CYP2C9 (IC50=9.7 μM). Compared to PPARα, fenofibrate has a greater affinity for cytochrome P450 epoxygenase (CYP)2C and inhibits it. Fenofibrate is a well-known PPARα agonist, but it also appears to be a strong inhibitor of cytochrome P450 epoxygenase (CYP)2C, according to an in vitro evaluation of 209 commonly given medications and related xenobiotics. Fenofibrate has >10 times the affinity for CYP2C (EC50=2.39±0.4 μM) compared to PPARα (EC50=30 μM). Low doses of fenofibrate reduce CYP2C8 activity without activating PPARα[2].

At a modest dose of 10 μg/g/day, fenofibrate suppresses CYP2C8 overexpression-induced retinal and choroidal neovascularization by 29% (P=0.021) and 36% (P=1.2×10−9), respectively, on a daily basis[2].

Absorption, Distribution and Excretion
A single 300mg oral dose of fenofibrate reaches a Cmax of 6-9.5mg/L with a Tmax of 4-6h in healthy, fasting volunteers.
5-25% of a dose of fenofibrate is eliminated in the feces, while 60-88% is eliminated in the urine. 70-75% of the dose recovered in the urine is in the form of fenofibryl glucuronide and 16% as fenofibric acid.
The volume of distribution of fenofibrate is 0.89L/kg, and can be as high as 60L.
The oral clearance of fenofibrate is 1.1L/h in young adults and 1.2L/h in the elderly.
Upon multiple dosing of fenofibrate, fenofibric acid steady state is achieved within 9 days. Plasma concentrations of fenofibric acid at steady state are approximately double those following a single dose. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.
The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration.
After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.
The metabolism and disposition of orally administered single doses of (14)C fenofibrate (isopropyl 2-[4-(4-chlorobenzoyl)phenoxy]-2- methylpropionate) have been studied in rat, guinea pig, and dog. In rats, the urinary excretion of (14)C in 5 days varied from 11 to 51% of the dose and was markedly dependent upon the dose form given. The interpretation of these data in terms of factors affecting the absorption of fenofibrate from the gut is complicated by the enterohepatic recirculation of metabolites. The tissue distribution of (14)C after oral administration of an ethanolic solution of fenofibrate has been studied in the rat. The only tissues in which the concentration of (14)C exceeded that in the blood were the organs of absorption and elimination, the gut, liver, and kidneys. Guinea pigs excreted 53% of the dose in the urine in 5 days, with a further 34% in the feces, while in dogs the corresponding figures were 9% and 81%, respectively. In all three species, all the urinary metabolites were products of ester hydrolysis, and the principal excretion product was "reduced fenofibric acid" which arose by subsequent carbonyl reduction. Glucuronidation of fenofibric acid and "reduced fenofibric acid" was a very minor reaction in the rat and guinea pig and was not detected in the dog. In addition, polar unknown metabolite(s) were detected in all three species, but were not investigated further. The results are discussed in terms of the comparative disposition of fenofibrate and other hypolipidemic agents and the contribution of these findings to the safety assessment of such drugs.

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Metabolism / Metabolites
Fenofibrate is completely hydrolyzed by liver carboxylesterase 1 to fenofibric acid. Fenofibric acid is either glucuronidated or has its carbonyl group reduced to a benzhydrol that is then glucuronidated. Glucuronidation of fenofibrate metabolites is mediated by UGT1A9. Reduction of the carbonyl group is primarily mediated by CBR1 and minorly by AKR1C1, AKR1C2, AKR1C3, and AKR1B1.
... The metabolism of fenofibrate was investigated in cynomolgus monkeys by ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS)-based metabolomics. Urine samples were collected before and after oral doses of fenofibrate. The samples were analyzed in both positive-ion and negative-ion modes by UPLC-QTOFMS, and after data deconvolution, the resulting data matrices were subjected to multivariate data analysis. Pattern recognition was performed on the retention time, mass/charge ratio, and other metabolite-related variables. Synthesized or purchased authentic compounds were used for metabolite identification and structure elucidation by liquid chromatography tandem mass spectrometry. Several metabolites were identified, including fenofibric acid, reduced fenofibric acid, fenofibric acid ester glucuronide, reduced fenofibric acid ester glucuronide, and compound X. Another two metabolites (compound B and compound AR), not previously reported in other species, were characterized in cynomolgus monkeys. More importantly, previously unknown metabolites, fenofibric acid taurine conjugate and reduced fenofibric acid taurine conjugate were identified, revealing a previously unrecognized conjugation pathway for fenofibrate.
Fenofibrate has been widely used for the treatment of dyslipidemia with a long history. Species differences of its metabolism were reported, but its metabolites in rodent have not been fully investigated. Urine and plasma samples were collected before and after oral dosages of fenofibrate in Sprague-Dawley rats. Urine samples were subjected to ultra-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS) analysis, and projection to latent structures discriminant analysis was used for the identification of metabolites. New metabolites in urine and plasma were also studied by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The metabolism pathway was studied in rat hepatocytes. Synthesized and purchased authentic compounds were used for metabolite identification by LC-MS/MS. Five ever-reported metabolites were identified and another four new ones were found. Among these new metabolites, fenofibric acid taurine and reduced fenofibric acid taurine indicate new phase II conjugation pathway of fenofibrate.
Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma. Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine. In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.
The metabolism and disposition of orally administered single doses of (14)C fenofibrate (isopropyl 2-[4-(4-chlorobenzoyl)phenoxy]-2- methylpropionate) have been studied in rat, guinea pig, and dog. In rats, the urinary excretion of (14)C in 5 days varied from 11 to 51% of the dose and was markedly dependent upon the dose form given. The interpretation of these data in terms of factors affecting the absorption of fenofibrate from the gut is complicated by the enterohepatic recirculation of metabolites. The tissue distribution of (14)C after oral administration of an ethanolic solution of fenofibrate has been studied in the rat. The only tissues in which the concentration of (14)C exceeded that in the blood were the organs of absorption and elimination, the gut, liver, and kidneys. Guinea pigs excreted 53% of the dose in the urine in 5 days, with a further 34% in the feces, while in dogs the corresponding figures were 9% and 81%, respectively. In all three species, all the urinary metabolites were products of ester hydrolysis, and the principal excretion product was "reduced fenofibric acid" which arose by subsequent carbonyl reduction. Glucuronidation of fenofibric acid and "reduced fenofibric acid" was a very minor reaction in the rat and guinea pig and was not detected in the dog. In addition, polar unknown metabolite(s) were detected in all three species, but were not investigated further. The results are discussed in terms of the comparative disposition of fenofibrate and other hypolipidemic agents and the contribution of these findings to the safety assessment of such drugs.
Route of Elimination: Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate and 25% was excreted in the feces.
Half Life: 20 hours

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Biological Half-Life
Fenofibric acid, the active metabolite of fenofibrate, has a half life of 23 hours. Fenofibrate has a half life of 19-27 hours in healthy subjects and up to 143 hours in patients with renal failure.
Fenofibric acid is eliminated with a half-life of 20 hours, allowing once daily administration in a clinical setting. /Fenofibric acid/

Toxicity Summary
Fenofibrate exerts its therapeutic effects through activation of peroxisome proliferator activated receptor a (PPARa). This increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III. The resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles, to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly.

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Hepatotoxicity
Mild, transient serum aminotransferase elevations develop in up to 20% of patients receiving fenofibrate, but values above 3 times normal in only 3% to 5%. These abnormalities are usually asymptomatic and transient, resolving even with continuation of fenofibrate, but they occasionally may require drug discontinuation. Monitoring of aminotransferase levels is recommended for patients receiving fenofibrate and discontinuation if enzymes persist above 3 times the upper limit of normal (ULN).
There have also been multiple reports of clinically apparent liver injury in patients on fenofibrate. Onset of injury is variable; cases resembling acute hepatitis usually arise within a few weeks or months of starting therapy (Case 2), whereas cases resembling chronic hepatitis and cirrhosis typically arise after more than 6 months or even years of treatment (Case 1). The pattern of serum enzyme elevations is typically hepatocellular, but both mixed and cholestatic patterns have also been described. Some instances of acute injury with a short latency (2 to 8 weeks) are associated with fever, rash and eosinophilia, suggesting immunoallergic hepatitis. Cases with a longer latency typically present with nonspecific symptoms of weakness and fatigue, have autoimmune features with hyperglobulinemia, smooth muscle or antinuclear antibody, and a chronic hepatitis-like clinical and histological picture that is sometimes prolonged and associated with significant fibrosis or cirrhosis.
Likelihood score: B (very likely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No relevant published information exists on the use of fenofibrate during breastfeeding. Because of a concern with disruption of infant lipid metabolism, fenofibrate is best avoided during breastfeeding. An alternate drug is preferred, especially while nursing a newborn or preterm infant. The manufacturer recommends that breastfeeding be avoided during fenofibrate therapy and for 5 days after the final dose.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Fenofibrate is 99% protein bound in serum, primarily to albumin.

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Toxicity Data
LD₅₀=1600 mg/kg (Oral, in mice)

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Interactions
Caution should be exercised when anticoagulants are given in conjunction with Tricor because of the potentiation of coumarin-type anticoagulants in prolonging the prothrombin time/INR. The dosage of the anticoagulant should be reduced to maintain the prothrombin time/INR at the desired level to prevent bleeding complications. Frequent prothrombin time/INR determinations are advisable until it has been definitely determined that the prothrombin time/INR has stabilized.
Increased risk of adverse musculoskeletal effects (i.e., increased CK, myoglobinuria, rhabdomyolysis). Avoid concomitant use unless potential benefit outweighs risk. Pharmacokinetic interaction reported following concomitant use with atorvastatin (decreased area under the plasma concentration-time curve [AUC] of atorvastatin) or pravastatin (increased peak plasma concentration and AUC of pravastatin).
Increased risk of cyclosporine-induced nephrotoxicity (i.e., deterioration in renal function). Use with caution.
Potential pharmacokinetic interaction (decreased absorption of fenofibrate). Fenofibrate should be administered 1 hour before or 4-6 hours after a bile acid sequestrant.
For more Interactions (Complete) data for Fenofibrate (7 total), please visit the HSDB record page.

[1]. Pharmacoepidemiologic and in vitro evaluation of potential drug-drug interactions of sulfonylureas with fibrates and statins. Br J Clin Pharmacol. 2014 Sep;78(3):639-48.

[2]. Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C Activity to Suppress Pathological Ocular Angiogenesis. EBioMedicine. 2016 Sep 30. pii: S2352-3964(16)30448-0.

Therapeutic Uses
Fenofibrate is used as an adjunct to dietary therapy to decrease elevated serum total and LDL-cholesterol, triglyceride, and apo B concentrations, and to increase HDL-cholesterol concentrations in the management of primary hypercholesterolemia and mixed dyslipidemia, including heterozygous familial hypercholesterolemia and other causes of hypercholesterolemia.
Fenofibrate also is used as an adjunct to dietary therapy in the management of patients with elevated serum triglyceride concentrations. Efficacy of the drug in reducing the risk of pancreatitis in patients with marked elevations in triglyceride concentrations (i.e., greater than 2000 mg/dL) has not been established. Fenofibrate is not indicated for use in patients with type I hyperlipoproteinemia who have elevated triglyceride and chylomicron concentrations but normal VLDL-cholesterol concentrations.
/EXPL THER/ Inflammation is implicated in chronic heart failure. In this study, the potential inhibitory effect of peroxisome proliferator-activated receptor-alpha (PPARalpha) activator fenofibrate on monocyte adhesion in chronic heart failure patients was investigated in vitro. ... Isolated peripheral blood mononuclear cells were collected from 36 patients (aged 65 +/- 8 years) with symptomatic chronic heart failure and from 12 healthy control subjects. The cultured human aortic endothelial cells were stimulated with or without 2 ng mL(-1) tumor necrosis factor-alpha (TNF-alpha) and the inhibitory effects of fenofibrate at 25, 50, 100 and 200 uM on endothelial mononuclear cell adhesion were tested. Furthermore, the human aortic endothelial cells were stimulated with 70% sera obtained from chronic heart failure patients and control individuals, respectively, with or without pretreatments with fenofibrate. The endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) was then confirmed by mRNA expression and Western blot. ... The increased adhesion of peripheral blood mononuclear cells to TNF-alpha-stimulated human aortic endothelial cells in chronic heart failure patients was reduced when the human aortic endothelial cells were pretreated with fenofibrate (31% inhibition, P = 0.0121). However, pretreatment of the isolated peripheral blood mononuclear cells collected from chronic heart failure patients with fenofibrate failed to suppress their adherence to TNF-alpha-stimulated human aortic endothelial cells. Furthermore, stimulation of cultured human aortic endothelial cells with chronic heart failure patient sera significantly increased VCAM-1 and ICAM-1 expression, which could also be inhibited by fenofibrate. The fenofibrate directly inhibits monocyte binding by TNF-alpha-activated human aortic endothelial cells, probably through preventing up-regulation of cell adhesion molecules by endothelial cells in response to inflammatory stimuli. This PPARalpha activator may have the potential to ameliorate vascular inflammation in patients with chronic heart failure.

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Drug Warnings
Severe rashes requiring hospitalization and corticosteroid therapy, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported rarely with fenofibrate in clinical studies. Urticaria and rash also have been reported in approximately 1% of patients receiving fenofibrate therapy in controlled trials.
Fenofibrate, like other fibric acid derivatives (e.g., gemfibrozil), may increase cholesterol excretion in bile, resulting in cholelithiasis. If gallbladder studies indicate the presence of gallstones, fenofibrate should be discontinued.
Liver function tests should be performed periodically (i.e., every 3 months) during the first 12 months of therapy. If serum aminotransferase concentrations of 3 times the upper limit of normal or higher persist, fenofibrate therapy should be discontinued.
Chronic active hepatitis and cholestatic hepatitis have occurred as early as several weeks and as late as several years after initiation of fenofibrate therapy; cirrhosis associated with chronic active hepatitis has been reported rarely with fenofibrate.
For more Drug Warnings (Complete) data for Fenofibrate (17 total), please visit the HSDB record page.

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Pharmacodynamics
Fenofibrate is a fibrate that activates peroxisome proliferator activated receptor alpha (PPARα) to alter lipid metabolism and treat primary hypercholesterolemia, mixed dyslipidemia, and severe hypertriglyceridemia. Fenofibrate requires once daily dosing and has a half life of 19-27 hours so its duration of action is long. Fenofibrate capsules are given at a dose of 50-150mg daily so the therapeutic index is wide. Patients should be counselled about the risk of rhabdomyolysis, myopathy, and cholelithiasis when taking fibrates.

C20H21CLO4

360.83

360.112

49562-28-9

Fenofibrate (Standard);49562-28-9;Fenofibrate;49562-28-9;Fenofibrate-d6;1092484-56-4;Fenofibrate-d4;1092484-57-5

3339

White to off-white solid powder

1.2±0.1 g/cm3

469.8±35.0 °C at 760 mmHg

80-81ºC

165.4±24.9 °C

0.0±1.2 mmHg at 25°C

1.547

4.8

0

4

7

25

458

0

YMTINGFKWWXKFG-UHFFFAOYSA-N

InChI=1S/C20H21ClO4/c1-13(2)24-19(23)20(3,4)25-17-11-7-15(8-12-17)18(22)14-5-9-16(21)10-6-14/h5-13H,1-4H3

propan-2-yl 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.93 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (6.93 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.93 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 33.33 mg/mL (92.37 mM) in Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)