clofibrate

Action and Spectrum

Actions and Spectrum: 

Actions: 

• Lipid-Lowering Effects: clofibrate primarily works by activating peroxisome proliferator-activated receptors (PPARs), specifically PPAR-alpha. This activation causes changes in gene expression, increasing the synthesis of enzymes involved in lipid metabolism. As a result, clofibrate reduces the production of triglycerides in the liver and increases the breakdown of triglyceride-rich particles, such as very low-density lipoprotein (VLDL). This helps lower triglyceride and cholesterol levels, especially low-density lipoprotein (LDL) cholesterol. 
• Modulation of Lipoprotein Lipase (LPL) Activity: clofibrate may increase lipoprotein lipase activity. This enzyme causes triglyceride breakdown in the blood vessels, which further aids in reducing triglyceride levels. 

Spectrum: 

While clofibrate was once widely prescribed for lipid-lowering purposes, its use has significantly decreased over the years due to several factors. The drug has been primarily replaced by other more effective and safer lipid-lowering agents, such as statins (HMG-CoA reductase inhibitors). Some important points regarding the spectrum of clofibrate include: 

• Triglyceride Lowering: clofibrate effectively lowers high triglyceride levels in the blood, especially in individuals with hypertriglyceridemia. 
• Moderate LDL Cholesterol Lowering: While clofibrate can modestly reduce LDL cholesterol levels, it is less effective than statins. 
• HDL Cholesterol Increase: clofibrate can increase HDL cholesterol levels, which benefits cardiovascular health. 
• Adverse Effects: clofibrate has several side effects, including gastrointestinal disturbances, liver function abnormalities, and an increased risk of gallstones. Additionally, some studies have raised concerns about an increased risk of certain cancers, particularly liver cancer, with long-term clofibrate use. Due to these safety concerns, the use of clofibrate has declined significantly. 
• Drug Interactions: clofibrate may interact with other medications, so informing your healthcare provider about all your drugs is essential to avoid potential adverse interactions. 

Drug Interaction

Adverse Reaction

Frequency not defined 

Anorexia 

Gastric discomfort 

Headache 

Dizziness 

Thrombocytopenia 

Mytotoxicity 

Diarrhea 

Vomiting 

Flatulence 

Drowsiness 

Leucopenia 

Hepatomegaly 

Skin reactions 

Dyspepsia 

Black Box Warning

Black Box Warning: 

None

Contraindication / Caution

Contraindication/Caution: 

Contraindications: 

• Hypersensitivity to clofibrate: Individuals with known hypersensitivity or allergy to clofibrate or its components should not use this medication. 
• Gallbladder Disease: clofibrate has been associated with an increased risk of gallstones and gallbladder disease. Therefore, it is generally contraindicated in individuals with gallbladder issues. 
• Liver Disease: clofibrate can cause liver function abnormalities, and its use is contraindicated in individuals with significant liver disease or a history of liver problems. 
• Severe Renal Impairment: clofibrate is primarily excreted through the kidneys, and its use should be avoided in individuals with severe kidney impairment. 
• Pregnancy and Breastfeeding: clofibrate is not recommended during pregnancy and breastfeeding due to potential risks to the fetus and infant. Alternative medications should be considered under medical supervision if lipid-lowering treatment is required during pregnancy or lactation. 

Cautions: 

• Drug Interactions: ergotamine can interact with various medications, including certain antifungal drugs, macrolide antibiotics, protease inhibitors, and others, leading to increased ergotamine levels and a higher risk of adverse effects. 
• Other Medical Conditions: Individuals with uncontrolled hypertension, renal impairment, liver impairment, or certain heart conditions may require cautious use of ergotamine. 

Pregnancy / Lactation

Pregnancy consideration:  

The drug is contraindicated during pregnancy. 

Breastfeeding warnings:  

The drug is contraindicated during lactation. 

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 
• Category B: No evidence of risk to the fetus is found in animal reproduction studies, and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for a human product; Pregnant women must take care of the potential risks. 
• Category D: There is adequate data with sufficient evidence of human fetal risk from various platforms. However, despite potential dangers may be used only in emergencies for potential benefits. 
• Category X: Drugs listed in this category outweigh the risks over benefits. The drug is not for pregnant women. 
• Category N: No data for the drug under this category is available. 

Pharmacology

Pharmacology: 

• Reduction of Triglycerides (TG): clofibrate increases the synthesis of lipoprotein lipase (LPL), an enzyme responsible for breaking down triglycerides into free fatty acids. This increases the clearance of triglyceride-rich particles from the blood, such as very low-density lipoprotein (VLDL) and chylomicrons, decreasing serum triglyceride levels. 
• Increase in High-Density Lipoprotein (HDL) Cholesterol: clofibrate can raise HDL cholesterol levels by enhancing the synthesis of apolipoprotein AI and AII, the main structural proteins of HDL particles. Increased HDL levels are associated with a reduced risk of atherosclerosis and cardiovascular disease. 
• Modest Reduction of Low-Density Lipoprotein (LDL) Cholesterol: While clofibrate primarily targets triglycerides and HDL cholesterol, it may also have a modest effect in lowering LDL cholesterol levels, though not as potent as statins (HMG-CoA reductase inhibitors). 

Pharmacodynamics: 

Activation of PPAR-alpha: 

clofibrate is a PPAR-alpha agonist which binds to and activates PPAR-alpha receptors. PPAR-alpha is primarily found in tissues involved in lipid metabolism, such as the liver, adipose tissue (fat cells), and muscle cells. 

Modulation of Gene Expression: 

Upon activation by clofibrate, PPAR-alpha forms a heterodimer with another receptor, retinoid X receptor (RXR), and together, they bind to specific DNA sequences known as PPAR response elements (PPREs) in the promoter regions of target genes. This binding leads to the modulation of gene expression, increasing the synthesis of various enzymes involved in lipid and lipoprotein metabolism. 

Pharmacokinetics: 

Absorption 

clofibrate is administered orally in the form of tablets or capsules. After ingestion, the drug gets absorbed from the GI tract into the bloodstream. The rate and extent of absorption varies among individuals and are influenced by factors such as food intake and formulation. 

Distribution 

clofibrate is distributed throughout the body via the bloodstream. It can cross the blood-brain barrier and the placenta and is also found in breast milk. The drug has a relatively large volume of distribution, which means it can distribute widely into various tissues. 

Metabolism 

clofibrate undergoes extensive metabolism in the liver. The primary metabolic pathway involves glucuronidation, where the drug is conjugated with glucuronic acid, forming inactive metabolites. The primary active metabolite of clofibrate is chlorophenoxyisobutyrate (CPIB). The metabolism of clofibrate can be influenced by various factors, including liver function and drug interactions with other medications. 

Elimination and Excretion 

The elimination of clofibrate and its metabolites occurs mainly through the kidneys. The drug and its metabolites get excreted in the urine.

Adminstartion

Administration: 

clofibrate was typically administered orally in the form of tablets or capsules. A healthcare professional determines the recommended dose and dosing frequency based on the patient’s lipid profile and response to treatment. 

Patient Information Leaflet

Patient information leaflet 

Generic Name:  clofibrate 

Pronounced: klo-fyb-rate 

Why do we use clofibrate? 

• Triglyceride Lowering: clofibrate effectively reduced elevated triglyceride levels in the blood as they are associated with an increased risk of cardiovascular disease. 
• HDL Cholesterol Increase: clofibrate increased HDL cholesterol levels, often called “good” cholesterol. HDL helps in removal of excess cholesterol from the bloodstream, reducing the risk of atherosclerosis and cardiovascular disease. 
• Management of Lipid Disorders: clofibrate was considered an option for patients who did not respond well to other lifestyle modifications, such as diet and exercise, or those who could not tolerate other lipid-lowering medications. 
• Combined Dyslipidemia: In some cases, clofibrate was used with other lipid-lowering agents to address combined dyslipidemia, where multiple lipid abnormalities were present. 
• Familial Combined Hyperlipidemia (FCH): clofibrate was sometimes prescribed for individuals with familial combined hyperlipidemia, a genetic disorder characterized by elevated levels of both triglycerides and LDL cholesterol. 
• Research and Clinical Studies: clofibrate has been used in clinical studies and research to investigate its effects on lipid metabolism and cardiovascular outcomes.