Fibrates: MOA and Pharmacophore Flashcards

Questions and Answers

What is the mechanism of action (MOA) of fibrates?

Agonist at nuclear hepatic (PPARa) results in increased expression of lipoprotein lipase, which decreases triglycerides.

What bonding occurs at the fibrate receptor?

Carboxylate and TYR (ion-ion bond).

What supporting bonds are involved for the fibrate receptor?

Ser, Tyr, His with carboxylate (H bonding); Phe, Leu, Ile, Val with various other hydrophobic portions.

What is the pharmacophore for fibrates?

Phenoxyisobutyric acids. Signup and view all the answers

What are the characteristics of gemfibrozil?

Lipophilic spacer, rapidly absorbed and extracted, food-dependent absorption, vulnerable to CYP3A4 benzylic hydroxylation, BID dosing, excreted as glucuronide ester. Signup and view all the answers

What describes fenofibrate?

Requires hydrolysis to be active, higher log P despite spacer, food-dependent, once daily dosing, excreted as glucuronide ester, no oxidative metabolism. Signup and view all the answers

What is the metabolism process for gemfibrozil?

O-demethylation by CYP3A4 fairly quickly, alcohol and aldehyde dehydrogenase, glucuronic acid conjugation. Signup and view all the answers

How is fenofibrate metabolized?

Activated via hydrolysis, glucuronic acid conjugation, longer half-life. Signup and view all the answers

What issue arises with fenofibrate absorption?

High lipophilicity surpasses optimal level. Signup and view all the answers

What are drug-drug interactions (DDIs) associated with gemfibrozil?

CYP 3A4 substrates, inhibitors, inducers. Signup and view all the answers

Gemfibrozil coadministered with statins increases the risk of muscle toxicity.

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The combination of gemfibrozil and ezetimibe is contraindicated for patients with gallstones.

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What happens when fibrates are combined with bile acid sequestrants (BAS)?

Sequestered action; BAS inactivate the anions of fibrates by binding to them. Signup and view all the answers

Study Notes

Fibrate Mechanism of Action

Fibrates act as agonists at nuclear hepatic receptor PPARa, increasing expression of lipoprotein lipase.
This mechanism leads to a reduction in triglyceride levels in the bloodstream.

Anchoring Bond to Fibrate Receptor

Interaction involves a carboxylate group forming an ion-ion bond with a tyrosine (Tyr) residue.

Supporting Bonds for Fibrate Receptor

Hydrogen bonding occurs between Serine (Ser), Tyr, and Histidine (His) with the carboxylate group.
Additional hydrophobic interactions are provided by Phenylalanine (Phe), Leucine (Leu), Isoleucine (Ile), and Valine (Val).

Pharmacophore Characteristics

The pharmacophore of fibrates is identified as phenoxyisobutryric acids.

Gemfibrozil Overview

Gemfibrozil is lipophilic with a rapidly absorbed profile and demonstrates food-dependent absorption.
It is susceptible to CYP3A4 metabolism through benzylic hydroxylation and requires bid dosing.
Excretion occurs as a glucuronide ester.

Fenofibrate Overview

Fenofibrate, a prodrug, must undergo hydrolysis for activation and has a higher log P than gemfibrozil despite also being lipophilic.
It has food-dependent absorption, can be dosed once daily, and is excreted as a glucuronide ester without oxidative metabolism.

Gemfibrozil Metabolism

Metabolized primarily through O-demethylation via CYP3A4.
Further processing includes alcohol and aldehyde dehydrogenase activity, leading to glucuronic acid conjugation, which competes with statins for UGT 1A1 and 1A3.
It has a relatively short half-life.

Fenofibrate Metabolism

Activation occurs through hydrolysis, followed by glucuronic acid conjugation without competition with statins.
It possesses a longer half-life, allowing for once-daily dosing.

Absorption Issues with Fenofibrate

Fenofibrate's high lipophilicity exceeding optimal levels can hinder absorption.
This can potentially be remedied by modifying particle size or creating soluble salts.

Drug-Drug Interactions with Gemfibrozil

Gemfibrozil interacts with CYP 3A4 substrates, inhibitors, and inducers, affecting other drug metabolism.

Muscle Toxicity Risks

Co-administration of gemfibrozil with statins increases the risk of muscle toxicity, especially with all statins except fluvastatin.
This is due to competition for UGT1A1 and 1A3, raising statin plasma levels.

Contraindications for Gallstone Patients

The combination of gemfibrozil with ezetimibe raises the risk of gallstone (cholelithiasis) formation and is contraindicated.

Combination of Fibrates and Bile Acid Sequestrants (BAS)

Fibrates and BAS have a sequestered action where BAS (cationic) inactivate fibrate anions by binding to them, reducing fibrate effectiveness.

Description

Test your knowledge on the mechanism of action and pharmacophore of fibrates with these flashcards. Each card covers key concepts like receptor binding and specific amino acid interactions. Perfect for students studying pharmacology or related fields.