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In a randomized crossover study, 24 SLCO181-genotyped healthy volunteers were given daily doses of 1,200 mg gemfibrozil, 40 mg atorvastatin, or placebo, followed by 0.25 mg of repaglinide on day 3. The mean increase in the repaglinide area under the plasma concentration-time curve from 0 hr to infinity (AUC(0-infinity)) produced by gemfibrozil was larger in individuals with the SLCO1B1 c.521CC genotype (n = 6) than in those with the c.521TC (n = 6) and c.521TT (n = 12) genotypes, by factors of 1.56 (P = 0.004) and 1.54 (P = 0.002), respectively. Gemfibrozil prolonged the repaglinide elimination half-life 1.43 times more in the c.521 CC group than in the c.521TT group (P = 0.047), but no differences were seen in the effects on peak plasma concentration (C(max)). While on gemfibrozil, the minimum blood glucose concentration after repaglinide intake was 19% lower in the c.521CC participants than in the c.521TT participants (P = 0.009). In the c.521TT group, atorvastatin intake had the effect of increasing repaglinide Cmax and AUC(0-infinity) by 41% (P = 0.001) and 18% (P = 0.033), respectively. In conclusion, the extent of gemfibrozil-repaglinide interaction depends on SLCO1B1 genotype. Atorvastatin raises plasma repaglinide concentrations, probably by inhibiting organic anion transporting polypeptide 1B1 (OATP1B1).

... In a randomized crossover study, 12 healthy volunteers received twice daily for 3 days either 600 mg gemfibrozil, 100 mg itraconazole (first dose 200 mg), both gemfibrozil and itraconazole, or placebo. On day 3 they ingested a 0.25 mg dose of repaglinide. Plasma drug and blood glucose concentrations were followed for 7 hr and serum insulin and C-peptide concentrations for 3 hr postdose. Gemfibrozil raised the area under the plasma concentration-time curve (AUC) of repaglinide 8.1-fold (range 5.5- to 15.0-fold; p<0.001) and prolonged its half-life (t(1/2)) from 1.3 to 3.7 hr (p<0.001). Although itraconazole alone raised repaglinide AUC only 1.4-fold (1.1- to 1.9-fold; p<0.001), the gemfibrozil-itraconazole combination raised it 19.4-fold (12.9- to 24.7-fold) and prolonged the t(1/2) of repaglinide to 6.1 hr (p<0.001). Plasma repaglinide concentration at 7 hr was increased 28.6-fold by gemfibrozil and 70.4-fold by the gemfibrozil-itraconazole combination (p<0.001). Gemfibrozil alone and in combination with itraconazole considerably enhanced and prolonged the blood glucose-lowering effect of repaglinide; i.e., repaglinide became a long-acting and stronger antidiabetic. Clinicians should be aware of this previously unrecognised and potentially hazardous interaction between gemfibrozil and repaglinide. Concomitant use of gemfibrozil and repaglinide is best avoided. If the combination is considered necessary, repaglinide dosage should be greatly reduced and blood glucose concentrations carefully monitored.

Concomitant administration of gemfibrozil 600 mg and a single 0.25-mg dose of repaglinide (dosage strength not commercially available in the US) in healthy individuals receiving gemfibrozil 600 mg twice daily for 3 days increased repaglinide AUC by 8.1-fold and prolonged the half-life of repaglinide from 1.3 to 3.7 hours. When both gemfibrozil and itraconazole were co-administered with repaglinide, the AUC of repaglinide was increased 19-fold and repaglinide half-life was prolonged to 6.1 hours. Plasma repaglinide concentration at 7 hours increased 28.6-fold with concomitant gemfibrozil administration and 70.4-fold with concomitant gemfibrozil-itraconazole therapy. Gemfibrozil therapy should not be initiated in patients taking repaglinide, and those taking gemfibrozil should not begin therapy with repaglinide, since such concomitant use may enhance and prolong the hypoglycemic effects of repaglinide. In addition, because of the apparent synergistic inhibitory effect of gemfibrozil and itraconazole on repaglinide metabolism, patients already receiving concomitant therapy with repaglinide and gemfibrozil should not receive itraconazole.

Myopathy and/or fatal or nonfatal rhabdomyolysis has occurred with combined gemfibrozil and statin (e.g., cerivastatin [no longer commercially available], lovastatin) therapy.

For more Interactions (Complete) data for Gemfibrozil (15 total), please visit the HSDB record page.

Mild, transient serum aminotransferase elevations develop in approximately 20% of patients receiving gemfibrozil, but values above 3 times normal in 5% or less. These abnormalities are usually asymptomatic and transient, resolving even with continuation. However, there have also been rare reports of clinically apparent liver injury in patients on long term gemfibrozil. The clinical presentation was highly variable. The onset of injury varied from a few weeks to several years after starting the medication and the pattern of serum enzyme elevations ranged from hepatocellular (Case 1) to mixed to cholestatic. Cases have not been associated with signs of immunoallergic (fever, rash, eosinophilia) or autoimmune hepatitis and recovery has been prompt and complete with stopping therapy.

EC50; Species: Chlorella vulgaris (Green algae, exponential growth phase); Conditions: freshwater, static, 22 °C; Concentration: 778 uM for 24 hr; Effect: decreased population growth rate /formulation/

EC50; Species: Chlorella vulgaris (Green algae, exponential growth phase, 1000000 cells/mL); Conditions: freshwater, static, 22 °C; Concentration: 643 uM for 48 hr; Effect: decreased population growth rate /formulation/

EC50; Species: Chlorella vulgaris (Green algae, exponential growth phase, 1000000 cells/mL); Conditions: freshwater, static, 22 °C; Concentration: 600 uM for 72 hr; Effect: decreased population growth rate /formulation/

EC50; Species: Daphnia magna (Water flea); Conditions: freshwater, static, 20 °C; Concentration: 228 uM for 24 hr; Effect: intoxication, immobilization /formulation/

For more Ecotoxicity Values (Complete) data for Gemfibrozil (6 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 430(SRC), determined from a structure estimation method(2), indicates that gemfibrozil is expected to have moderate mobility in soil(SRC). The estimated pKa of gemfibrozil is 4.5(3), indicating that this compound will almost entirely exist in the anion form and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the acid exists as an anion and anions do not volatilize. Gemfibrozil is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.1X10-5 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Gemfibrozil was 69% removed during passage through a municipal sewage treatment plant; however, removal could be attributed to adsorption to sludge(6).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 430(SRC), determined from a structure estimation method(2), indicates that gemfibrozil is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 4.5(3) indicates gemfibrozil will exist almost entirely in the anion form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from an estimated log Kow of 4.8(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Gemfibrozil was 69% removed during passage through a municipal sewage treatment plant; however, removal could also be attributed to adsorption to sludge(8).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), gemfibrozil, which has an estimated vapor pressure of 3.1X10-5 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase gemfibrozil is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 5 hrs(SRC), calculated from its rate constant of 8.2X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase gemfibrozil may be removed from the air by wet or dry deposition(SRC). Gemfibrozil does not contain chromophores that absorb at wavelengths >290 nm(4) and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Dyspepsia was reported in approximately 20 percent of patients on gemfibrozil. The most common reported adverse effects are fatigue, rash, atrial fibrillation, eczema, abdominal pain, nausea, vomiting, diarrhea, vertigo, constipation, and headache. Less frequent (less than 1 percent) reported adverse effects are myalgia, rhabdomyolysis (more frequent if coadministering gemfibrozil with a statin), acute appendicitis, cholelithiasis, angioedema, hypokalemia, eosinophilia, myopathy, synovitis, taste disturbance, xerostomia, flatulence.

Adverse drug reactions from overdose can include diarrhea, peripheral neuropathy, hyperkalemia, myopathy, renal failure, rhabdomyolysis, elevation in liver function tests, and opacities in the eye lens. The treatment is mainly supportive. A case of overdose with 9 gm gemfibrozil is reported in a seven-year-old child followed by complete recovery.

Gemfibrozil increases the activity of extrahepatic lipoprotein lipase (LL), thereby increasing lipoprotein triglyceride lipolysis. It does so by activating Peroxisome proliferator-activated receptor-alpha (PPAR‘±) 'transcription factor ligand', a receptor that is involved in metabolism of carbohydrates and fats, as well as adipose tissue differentiation. This increase in the synthesis of lipoprotein lipase thereby increases the clearance of triglycerides. Chylomicrons are degraded, VLDLs are converted to LDLs, and LDLs are converted to HDL. This is accompanied by a slight increase in secretion of lipids into the bile and ultimately the intestine. Gemfibrozil also inhibits the synthesis and increases the clearance of apolipoprotein B, a carrier molecule for VLDL.

/AQUATIC SPECIES/ Human and veterinarian pharmaceuticals have been detected in the aquatic environment for a number of years, but the potential for biological effects in exposed aquatic organism is only now being reported. The lipid regulator, gemfibrozil (GEM) is detected at ug/L concentrations in domestic wastewater and ng/L concentrations in surface waters. ...The uptake of GEM /was investigated/ in goldfish (Carassius auratus) over a 96 hr time period by measuring GEM in blood plasma using LC-MS/MS. Results indicated that GEM can be taken up from water through the gills. In goldfish exposed to GEM by a single intraperitoneal injection, concentrations of GEM in the blood plasma declined rapidly over 96 hr post-injection, with a half-life estimated at approximately 19 hr. Exposure of goldfish to waterborne GEM at an environmentally relevant concentration over 14 days resulted in a plasma bioconcentration factor of 113. In goldfish exposed to aqueous concentrations of GEM for 96 hr or 14 days, plasma testosterone (T) was reduced by over 50% in fish from all treatments. As a possible mechanistic explanation for the observed reduction in T, levels of steroid acute regulatory (StAR) protein transcript in goldfish testes were assessed by RT-PCR. StAR protein is involved in the transport of cholesterol from the outer to the inner mitochondrial membrane for transformation by the first enzyme in steroidogenesis. After exposure to GEM for 96 hr, a 50% decrease in StAR mRNA levels was observed in goldfish. Gonadal StAR mRNA levels were not affected in the 14 days exposure, indicating that the observed decreases in plasma testosterone were not solely due to impaired delivery of cholesterol to the inner mitochondrial membrane. Our results demonstrate that exposure to environmental levels of GEM leads to bioconcentration of the drug in plasma and the potential for endocrine disruption in fish.

/AQUATIC SPECIES/ The lipid regulator gemfibrozil (GEM) is one of many human pharmaceuticals found in the aquatic environment. We previously demonstrated that GEM bioconcentrates in blood and reduces plasma testosterone levels in goldfish (Carassius auratus). In this study, we address the potential of an environmentally relevant waterborne concentration of GEM (1.5 ug/L) to induce oxidative stress in goldfish liver and whether this may be linked to GEM acting as a peroxisome proliferator (PP). We also investigate the autoregulation of the peroxisome proliferator-activated receptors (PPARs) as a potential index of exposure. The three PPAR subtypes (alpha, beta, and gamma) were amplified from goldfish liver cDNA. Goldfish exposed to a concentration higher (1500 ug/L) than environmentally relevant for 14 and 28 days significantly reduce hepatic PPARbeta mRNA levels (p<0.001). Levels of CYP1A1 mRNA were unchanged. GEM exposure significantly induced the antioxidant defense enzymes catalase (p<0.001), glutathione peroxidase (p<0.001) and glutathione-S-transferase (p=0.006) but not acyl-CoA oxidase or glutathione reductase. As GEM exposure failed to increase levels of thiobarbituric reactive substances (TBARS), we conclude that a sub-chronic exposure to GEM upregulates the antioxidant defense status of the goldfish as an adaptive response to this human pharmaceutical.

Gemfibrozil was detected in sewage treatment plant effluents at concentrations of 1.34 and 0.06 ug/L (France), 0.71 ug/L (Greece), 0.81, 0.84, and 4.76 ug/L (Italy), and 2.07 ug/L (Sweden)(1). The median concentration in effluent from German municipal sewage treatment plants was 0.4 ug/L, max of 1.5 ug/L(2).

Gemfibrozil concentrations in final effluents of eight municipal sewage treatment plants, Atlantic Canada, sampled in 2003(1). [Table#7402]

Gemfibrozil was detected in 76 of 84 final sewage samples from 74 US publicly-owned treatment works generating more than one million gallons of wastewater per day. Samples were obtained between August 2006 and March 2007(1). Minimum and maximum concentrations were 12.1 and 2,650 ug/g dry-weight, respectively(1).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of gemfibrozil can be estimated to be 430(SRC). According to a classification scheme(2), this estimated Koc value suggests that gemfibrozil is expected to have moderate mobility in soil. The pKa of gemfibrozil is estimated as 4.5(3), indicating that this compound will exist almost entirely in the anion form in the environment and anions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/SIGNS AND SYMPTOMS/ Myopathy and/or fatal or nonfatal rhabdomyolysis has occurred with combined gemfibrozil and statin (e.g., cerivastatin [no longer commercially available], lovastatin) therapy.

/SIGNS AND SYMPTOMS/ The most frequent adverse effects of gemfibrozil involve the GI tract and occasionally may be severe enough to require discontinuance of the drug. Abdominal pain (and, in some instances, acute appendicitis), and epigastric pain or dyspepsia are common adverse GI effects reported with gemfibrozil. Nausea, vomiting, diarrhea, constipation, and flatulence occur less frequently; cholestatic jaundice also has been reported. Dry mouth, anorexia and/or weight loss, gas pain, pancreatitis, colitis, and heartburn have also been reported in patients receiving gemfibrozil but have not been directly attributed to the drug.

/CASE REPORTS/ A 49-year-old woman with chronic renal failure was given gemfibrozil for hyperlipidemia. She developed gemfibrozil-induced myositis which precipitated an acute compartment syndrome, necessitating emergency fasciotomy. The muscle biopsy showed prominent degeneration of the skeletal muscle fibers, associated with moderate chronic inflammatory infiltration. Electron microscopy revealed myofibrillary fragmentation and mitochondrial disorganization. The clinicopathologic features of gemfibrozil-induced myositis appear to be distinct from those of clofibrate-induced muscular syndrome. Extreme caution should be exercised in the use of gemfibrozil in patients with impaired renal function.

/CASE REPORTS/ A 30-year-old white man with hypertension, type 1 diabetes mellitus, and hyperlipidemia was hospitalized due to myalgias, nausea, and vomiting that began after he started working as a jackhammer operator 4 days previously. His medications were lisinopril, aspirin, insulin, and gemfibrozil. Creatine kinase and creatinine, which previously had been mildly elevated and normal, respectively, were markedly elevated, consistent with rhabdomyolysis with acute renal failure. ... Strenuous exertion, hypovolemia, and lisinopril use may have contributed to the severity of illness. An objective causality assessment revealed that an adverse drug reaction to gemfibrozil was possible. Gemfibrozil monotherapy of hyperlipidemia may predispose to rhabdomyolysis with acute renal failure.

For more Human Toxicity Excerpts (Complete) data for Gemfibrozil (9 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl gemfibrozil, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Medication: Lipid regulator

Medication

THERAP CAT: Antilipemic

Use (kg) in Switzerland (2009): >250

For treatment of adult patients with very high elevations of serum triglyceride levels (types IV and V hyperlipidemia) who are at risk of developing pancreatitis (inflammation of the pancreas) and who do not respond adequately to a strict diet.

It is prepared by reaction of the lithium salt of sodium or magnesium isobutyrate (made by reaction of the absolutely dry isobutyrates with butyllithium) with 3-(2,5-xylyloxy)propyl bromide.

Preparation: M. Hayashi et al., De 2700021; eidem, US 4052512 (both 1977 to Ono).