Gemfibrozil

Gemfibrozil is a lipid-lowering agent and belongs to the substance class of fibrates.

Significance: In contrast to statins, fibrates have only a minor effect on the LDL-C value, which plays a decisive role in cardiovascular risk, and have not been shown to improve prognosis.

Fibrates are therefore only used in very few indications, predominantly in cases of elevated triglyceride levels, and are used less frequently than satins and other lipid-lowering drugs. In addition, fibrates are very difficult to combine with other lipid-lowering drugs such as statins due to their complex WW profile, which further limits their applicability.

Mechanism of action: The exact mechanism of gemfibrozil's lipid-regulating activity is not fully understood.

Gemfibrozil stimulates peripheral lipolysis of triglyceride-rich lipoproteins such as VLDL and chylomicrons (by stimulation of LPL).

Gemfibrozil inhibits the synthesis of VLDL in the liver and increases HDL2 and HDL3 subfractions as well as apolipoproteins A-I and A-II. However, there is also evidence that gemfibrozil increases the turnover and breakdown of cholesterol from the liver!

Gemfibrozil is a non-halogenated phenoxypentanoic acid.

Absorption: orally rapid and complete with 100% bioavailability. Maximum plasma levels after 1 to 2 hours.

Plasma protein binding of gemfibrozil and its main metabolite is at least 97 %.

Metabolism: Gemfibrozil is oxidized by a ring methyl group and successively forms a hydroxymethyl and a carboxyl metabolite (as main metabolites). These have a low potency and an elimination half-life of approx. 20 hours. Glucuronidation to gemfibrozil 1-O-β-glucuronide is another important elimination pathway of gemfibrozil.
Enzymes involved in metabolism are not fully known. In vitro and in vivo studies have shown that gemfibrozil inhibits the enzymes CYP2C8, CYP2C9, CYP2C19, CYP1A2, UGTA1, UGTA3 and OATP1B1. Gemfibrozil 1-O-β-glucuronide also inhibits CYP2C8 and OATP1B1.

Elimination: Gemfibrozil is mainly eliminated by metabolization. Approximately 70% is excreted in the urine, mainly in the form of conjugates; less than 6% is excreted unchanged in the urine and approximately 6% of the dose is excreted via the intestine. The elimination half-life is 1.3 to 1.5 hours. In the therapeutic dosage range, the pharmacokinetics are linear.

Before considering drug therapy as first-line treatment, always make lifestyle changes, especially weight loss and reduction of saturated (animal) fats, exercise, alcohol cessation if necessary, and always first address treatment of an existing underlying causative disease such as diabetes, hypothyroidism, nephrotic syndrome, etc., as well as secondary hyperlipidemia with other drugs.

Additionally, only indicated as supportive treatment on a subordinate basis:

severe hypertriglyceridemia with or without low HDL cholesterol levels;

mixed hyperlipidemia, if hypertriglyceridemia is predominant and a statin is contraindicated or not tolerated;

in primary hypercholesterolemia when a statin is contraindicated or not tolerated, to reduce cardiovascular morbidity in men with elevated non-HDL cholesterol who are at high risk of a first cardiovascular event when a statin is contraindicated or not tolerated.

other alternatives may be considered as a priority.

For use in adults only; no studies/data available on children and adolescents

frequently: gastrointestinal complaints, dizziness, headache, eczema, rash.

occasionally: atrial fibrillation.

rarely: Rhabdomyolysis, myopathy, myositis, myasthenia, synovitis, myalgia, arthralgia, laryngeal edema, bone marrow failure, severe anemia, thrombocytopenia, leukopenia, eosinophilia, pancreatitis, appendicitis, cholestatic jaundice, Hepatitis, cholelithiasis,
cholecystitis, abnormal liver function values, angioedema, exfoliative dermatitis, urticaria, dermatitis, hair loss, photosensitivity, itching, depression, reduced libido, erectile dysfunction.

WW mainly due to concomitant use of CYP2C8(e.g. dabrafenib, enzalutamide, loperamide, montelukast, repaglinide, rosiglitazone, pioglitazone, dasabuvir, selexipag and paclitaxel) CYP2C9(e.g. warfarin and glimepiride), as well as CYP2C19, CYP1A2, UG-TA1, UGTA3 and OATP1B1 subunits.e.g. warfarin and glimepiride), as well as CYP2C19, CYP1A2, UG-TA1, UGTA3 and OATP1B1 substrates.

However, WW profile of gemfibrozil is diverse and complex as the metabolism of gemfibrozil is not fully known.

Gemfibrozil causes increased exposure of numerous drugs, when used concomitantly, through potent inhibition of the enzymes CYP2C8, CYP2C9, CYP2C19, CYP1A2 and UDP-glucuronyltransferase (UGTA1 and UGTA3) and also inhibits the organic anion-transporting polypeptide 1B1 (OATP1B1).

In addition, gemfibrozil is metabolized to gemfibrozil 1-O-β-glucuronide, which also inhibits CYP2C8 and OATP1B1!

Simultaneous use with statins should generally be avoided; some statins are contraindicated! Risk of severe myopathy, rhabdomyolysis with risk of kidney failure, also risk of liver damage with both substances and possibly potentiated by mutual WW!

Bioavailability of gemfibrozil may be reduced when administered at the same time as anion exchangeresins such as colestipol, therefore a minimum interval of 2 hours should be observed.

If antidiabetics(oral and insulin) are used at the same time, there is a risk of sudden hypoglycaemia; close blood glucose monitoring required! see also contraindications and specialist information! (e.g. also repaglinide + gemfibrozil or repaglinide + itroconazole + gemfibrozil)

the effect of vitamin K antagonists of the coumarin type such as warfarin, acenocoumarol or phenprocoumon can be enhanced, therefore careful monitoring of the prothrombin time (INR - International Normalized Ratio) is required! Use gemfibrozil only with caution at the same time; reduce the dose of anticoagulants if necessary!

Colchicine: risk of myopathy and rhabdomyolysis may be increased!

Enzalutamide: great caution with concomitant use; only if unavoidable, only with reduced dose, as risk of seizures increased!

Bexarotene; concomitant use not recommended!

Further WW must be clarified for each substance on a case-by-case basis!

Due to the high plasma protein binding, there is also the possibility of adverse drug reactions due to displacement reactions with other drugs, as well as increased efficacy in hypoalbuminemia!

For further information, see the specialist information!