Phenoxyisobutyric Acids (Fibrates) phenoxyisobutyrate (phibrate) MOA • activate peroxisome proliferator-activated receptor alpha (PPARα), a hepatic nuclear protein that regulates genes controlling fatty acid metabolism • PPARα stimulation enhances lipoprotein lipase expression • Triglyceride cleavage from VLDL, which facilitates receptor-mediated clearance • FFA oxidation. • Inhibition of triglyceride synthesis • decrease serum triglyceride and VLDL levels. • HDL levels increase • facilitate cholesterol removal from liver dimethylpentanoic acid
peroxisome proliferator-activated receptor peroxisome proliferator-activated receptor retinoic acid receptor
SAR-alpha gemfibrozil to be absorbed through the gastrointestinal membrane without the need of an ester prodrug aromatic ring with a chloro group or chlorine-containing cyclopropyl ring produces compounds with significantly longer half-lives.
Physicochemical Properties pKa is approximately 3.5→ anion predominates 2,5-dimethyl ring is predicted to be much more hydrophobic than the 4- chloro ring fenofibric acid
Metabolism Gemfibrozil : 1.5-hour elimination half-life requires twice-a-day dosing Fenofibrate :Steric hindrance from the branched alkyl moieties slows prodrug activation Fenofibrate and fenofibric acid are resistant to oxidation. The 22-hour elimination half-life → once-daily Gemfibrozil competes with all statins→ increasing the risk of serious toxicity
Physicochemical and Pharmacokinetic Properties • highly lipophilic→ distribute passively out of the gut and into the liver • Despite the lack of a hydrocarbon spacer, fenofibrate has a higher log P than gemfibrozil due to: • The carbon-rich nonionizable isopropylcarboxylate ester • The second phenyl ring and its p-chloro substituent. • Gemfibrozil must be given with meals (30 minutes prior to meals) • Fenofibrate’s dependency on food is formulation specific
DRUG–DRUG INTERACTIONS • Oral anticoagulants (increased International Normalized Ratio and risk of hemorrhage) • Statins (primarily gemfibrozil: inhibition of hepatic OATP1B1, increased risk of myopathy) • BAS (inhibition of fibrate intestinal absorption, if coadministered) • Ezetimibe (gemfibrozil: increased risk of cholelithiasis) • Antidiabetic agents (increased risk of hypoglycemia)
peroxisome proliferator-activated receptor • Alpha and Gamma (Activation of PPAR-γ causes insulin sensitization and enhances glucose metabolism)
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