Gemfibrozil

Gemfibrozil’s mechanism of action has not been definitively established. In man, gemfibrozil stimulates the peripheral lipolysis of triglyceride rich lipoproteins such as VLDL and cholymicrons (by stimulation of LPL). Gemfibrozil also inhibits synthesis of VLDL in the liver. Gemfibrozil increases the HDL2 and HDL3 subfractions as well as apolipoprotein A-I and A-II.

Gemfibrozil is a non-halogenated phenoxypentanoic acid. Gemfibrozil is a lipid regulating agent which regulates lipid fractions.

Animal studies suggest that the turnover and removal of cholesterol from the liver is increased by gemfibrozil.

There is evidence that treatment with fibrates may reduce coronary heart disease events but they have not been shown to decrease all cause mortality in the primary or secondary prevention of cardiovascular disease.

Absorption

Gemfibrozil is well absorbed from the gastro-intestinal tract after oral administration with a bioavailability close to 100%. As the presence of food alters the bioavailability slightly gemfibrozil should be taken 30 minutes before a meal. Peak plasma levels occur in one to two hours. After administration of 600 mg twice daily a C_max in the range 15 to 25 mg/L is obtained.

Distribution

Volume of distribution at steady state is 9-13 L. The plasma protein binding of gemfibrozil and its main metabolite are at least 97%.

Biotransformation

Gemfibrozil undergoes oxidation of a ring methyl group to form successively a hydroxymethyl and a carboxyl metabolite (the main metabolite). This metabolite has a low activity compared to the mother compound gemfibrozil and an elimination half-life of approximately 20 hours. Glucuronidation to gemfibrozil 1-O-β-glucuronide is another important elimination pathway for gemfibrozil in man.

The enzymes involved in the metabolism of gemfibrozil are not known. The interaction profile of gemfibrozil and its metabolites is complex. In vitro and in vivo studies have shown that gemfibrozil inhibits CYP2C8, CYP2C9, CYP2C19, CYP1A2, UGTA1, UGTA3 and OATP1B1. Gemfibrozil 1-O-β-glucuronide also inhibits CYP2C8 and OATP1B1.

Elimination

Gemfibrozil is eliminated mainly by metabolism. Approximately 70% of the administered human dose is excreted in the urine, mainly as conjugates of gemfibrozil and its metabolites. Less than 6% of the dose is excreted unchanged in the urine. Six percent of the dose is found in faeces. The total clearance of gemfibrozil is in the range 100 to 160 ml/min, and the elimination half-life is in the range 1.3 to 1.5 hours. The pharmacokinetics is linear within the therapeutic dose range.

Special patient groups

No pharmacokinetic studies have been performed in patients with impaired hepatic function.

There are limited data on patients with mild, moderate and non-dialysed severe renal impairment. The limited data support the use of up to 1200 mg a day in patients with mild to moderate renal failure not receiving another lipid lowering drug.

In a 2-year study of gemfibrozil, subcapsular bilateral cataracts occurred in 10%, and unilateral in 6.3%, of male rats treated at 10 times the human dose.

In a mouse carcinogenicity study at dosages corresponding to 0.1 and 0.7 times the clinical exposure (based on AUC), there were no significant differences from controls in the incidence of tumours. In a rat carcinogenicity study at dosages corresponding to 0.2 and 1.3 times the clinical exposure (based on AUC), the incidence of benign liver nodules and liver carcinomas was significantly increased in high dose males, and the incidence of liver carcinomas increased also in the low dose males, but this increase was not statistically significant.

Liver tumours induced by gemfibrozil and other fibrates in small rodents are generally considered to be related to the extensive proliferation of peroxisomes in these species and, consequently, of minor clinical relevance.

In the male rat, gemfibrozil also induced benign Leydig cell tumours. The clinical relevance of this finding is minimal.

In reproductive toxicity studies, administration of gemfibrozil at approximately 2 times the human dose (based on body surface area) to male rats for 10 weeks resulted in decreased fertility. Fertility was restored after a drug-free period of 8 weeks. Gemfibrozil was not teratogenic in either rats or rabbits. Administration of 1 and 3 times the human dose (based on body surface area) of gemfibrozil to female rabbits during organogenesis caused a dose-related decrease in litter size. Administration of 0.6 and 2 times the human dose (based on body surface area) of gemfibrozil to female rats from gestation Day 15 through weaning caused dose-related decreases in birth weight and suppression of pup growth during lactation. Maternal toxicity was observed in both species and the clinical relevance of decreases in rabbit litter size and rat pup weight is uncertain.