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Pharmaceuticals -> Antilipidemic Agents

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Used in Switzerland

Breast Feeding; Lactation; Milk, Human; Anticholesteremic Agents; Hypolipidemic Agents; Fibric acids

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

58-61

62 °C

61 - 63 °C

165.5 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

167.81 Ų [M+Na]+

This chemical does not meet GHS hazard criteria for 0.8% (1 of 133) of reports.

Warning

H302 (99.2%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P264, P270, P273, P280, P301+P317, P318, P330, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 133 reports by companies from 10 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

Hazard Traits - Carcinogenicity; Reproductive Toxicity

Status: Active Update: 13-03-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/23698

Gemfibrozil: Does not have an individual approval but may be used under an appropriate group standard

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.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

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.

/AQUATIC SPECIES/ Gemfibrozil is a lipid-regulating agent widely used in patients at risk of coronary disease. Pharmaceutical products, such as gemfibrozil, are found in municipal effluents and represent a major source of contamination. To date, there is little available information about the adverse effects of gemfibrozil in aquatic organisms. For this reason, the toxic effects were investigated using model systems from four trophic levels. The most sensitive system was the immobilization of Daphnia magna, with a non-observed adverse effect level of 30 uM and a mean effective concentration of 120 uM after 72 hr, followed by the inhibition of bioluminescence of Vibrio fischeri, the hepatoma fish cell line PLHC-1 line and the inhibition of the growth of Chlorella vulgaris. Although protein content, neutral red uptake, methylthiazol metabolization and lysosomal function were reduced in PLHC-1 cells, stimulations were observed for lysosomal function, metallothionein levels and succinate dehydrogenase, glucose-6-phosphate dehydrogenase and acetylcholinesterase activities. No changes were observed in ethoxyresorufin-O-deethylase activity. The main morphological alterations were hydropic degeneration and loss of cells. Modulation studies on gemfibrozil toxicity were also carried out. General antioxidants and calcium chelators did not modify the toxicity of gemfibrozil, whereas a Fe(III) chelator, a membrane permeable sulphydryl-protecting compound and glutathione level modifying agents did change the toxicity. One of the possible mechanisms of gemfibrozil toxicity seems to be the binding to sulphydryl groups, including those of glutathione. According to the result, gemfibrozil should be classified as harmful to aquatic organisms. However, comparing the concentrations in water and the toxicity quantified in the assayed systems, gemfibrozil is not expected to represent acute risk to the aquatic biota.

/AQUATIC SPECIES/ The high consumption of blood lipid regulators is leading to frequent reports of the occurrence of fibrates in natural streams and wastewater effluents. This paper describes a study undertaken to evaluate the acute toxicity of bezafibrate, clofibric acid, gemfibrozil, and fenofibric acid, a metabolite of fenofibrate whose ecotoxicity has not been previously reported. The bioassays used were based on Vibrio fischeri, Daphnia magna, and Anabaena CPB4337 tests. Anabaena CPB4337 is a novel bioassay based on Anabaena sp. PCC 7120 strain CPB4337 bearing in the chromosome a Tn5 derivative with luxCDABE from the luminescent terrestrial bacterium Photorhabdus luminescens. The higher toxicity corresponded to fenofibric acid, with EC50 as low as 1.72 mg/L for V. fischeri. Gemfibrozil was also toxic for Anabaena sp. with EC50 of 4.42 mg/L. The study reports the results from toxicity tests using fortified real wastewater samples taken from the effluent of a wastewater treatment plant. The wastewater itself was found to be very toxic to Anabaena CPB4337 (84% of bioluminescence inhibition) whereas it did not have any negative effect on D. magna or V. fischeri. On the contrary, V. fischeri luminescence exhibited a stimulatory effect in wastewater. Discussion Except for fenofibric acid, the Anabaena bioassay was more sensitive than the D. magna and V. fischeri bioassays to bezafibrate, clofibric acid, and gemfibrozil. For the three toxicity tests, fortification resulted in lower measured toxicity for the four compounds, probably indicating a reduced bioavailability due to the interaction with other chemicals in the wastewater or with particulate matter. The observed decrease in toxicity associated to the use of a wastewater matrix was higher for the more hydrophobic compounds reaching one order of magnitude for bezafibrate and gemfibrozil. The Anabaena CPB4337 bioassay revealed a certain risk associated with the three less toxic compounds tested. Based on V. fischeri and D. magna bioassays, bezafibrate and gemfibrozil would have been considered non-toxic and harmful, respectively. The use of EC50 data measured in wastewater increases the risk estimation. Recommendations and perspectives Cyanobacteria, as primary producers with a key role in the carbon and nitrogen cycles, are a substantial component of the microbial food webs. Any detrimental effect on this group may have a negative impact in nutrient availability to organisms of higher trophic levels and should be considered in ecotoxicity assessment tests.

For more Ecotoxicity Excerpts (Complete) data for Gemfibrozil (8 total), please visit the HSDB record page.

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.

C - Cardiovascular system

QC - Cardiovascular system

Gemfibrozil alters lipid metabolism to treat patients with hyperlipidemia. The duration of action requires twice daily dosing as the mean residence time of gemfibrozil is up to 9.6h in patients with chronic renal failure. Gemfibrozil has a wide therapeutic index as trials with twice the standard dose were not associated with severe side effects. Patients taking gemfibrozil may be at an increased risk of developing cholelithiasis and cholecystitis, as seen in patients taking [clofibrate].

Gemfibrozil activates peroxisome proliferator-activated receptor-α (PPARα), which alters lipid metabolism. This activation leads to increased HDL, apo AI, apo AII, lipoprotein lipase (LPL), inhibition of apo B synthesis, peripheral lipolysis, decreased removal of free fatty acids by the liver, and increased clearance of apoB. Upregulated LPL reduces plasma triglyceride levels. Decreased hepatic removal of fatty acids decreases the production of triglycerides. The effects on apoB synthesis and clearance decrease VLDL production which also reduce plasma triglyceride levels. Gemfibrozil's glucuronide metabolite is also an inhibitor of CYP2C8.

The present study underlines the importance of PI3K in mediating the anti-inflammatory effect of gemfibrozil, a prescribed lipid-lowering drug for humans, in mouse microglia. Gemfibrozil inhibited LPS-induced expression of inducible NO synthase (iNOS) and proinflammatory cytokines in mouse BV-2 microglial cells and primary microglia. By overexpressing wild-type and dominant-negative constructs of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) in microglial cells and isolating primary microglia from PPAR-alpha-/- mice, we have demonstrated that gemfibrozil inhibits the activation of microglia independent of PPAR-alpha. Interestingly, gemfibrozil induced the activation of p85alpha-associated PI3K (p110beta but not p110alpha) and inhibition of that PI3K by either chemical inhibitors or dominant-negative mutants abrogated the inhibitory effect of gemfibrozil. Conversely, overexpression of the constitutively active mutant of p110 enhanced the inhibitory effect of gemfibrozil on LPS-induced expression of proinflammatory molecules. Similarly, gemfibrozil also inhibited fibrillar amyloid beta (Abeta)-, prion peptide (PrP)-, dsRNA (poly IC)-, HIV-1 Tat-, and 1-methyl-4-phenylpyridinium (MPP+)-, but not IFN-gamma-, induced microglial expression of iNOS. Inhibition of PI3K also abolished the inhibitory effect of gemfibrozil on Abeta-, PrP-, poly IC-, Tat-, and MPP+-induced microglial expression of iNOS. Involvement of NF-kappaB activation in LPS-, Abeta-, PrP-, poly IC-, Tat-, and MPP+-, but not IFN-gamma-, induced microglial expression of iNOS and stimulation of IkappaBalpha expression and inhibition of NF-kappaB activation by gemfibrozil via the PI3K pathway suggests that gemfibrozil inhibits the activation of NF-kappaB and the expression of proinflammatory molecules in microglia via PI3K-mediated up-regulation of IkappaBalpha.

... After 2-4 months of gemfibrozil therapy in patients with type IIa, IIb, IV, or V hyperlipoproteinemia, HDL-apoprotein A-I (HDL-apoA-I) may be either unchanged or increased and HDL-apoprotein A-II (HDL-apoA-II) is increased. Unlike niacin, gemfibrozil has not been shown to reduce HDL2 catabolism. Gemfibrozil has been reported to increase the synthetic rates of HDL-apoA-I and HDL-apoA-II in patients with type V hyperlipoproteinemia. The HDL2 subfraction is increased to a greater degree than the HDL3 subfraction during gemfibrozil therapy. Low HDL2 concentrations have been reported to correlate with increased coronary heart disease. Gemfibrozil increases serum reserve cholesterol binding capacity (SRCBC), the capacity of serum to solubilize additional cholesterol, by about 60%. SRCBC exists in a subclass of HDL.31 In patients with types IIa, IIb, or IV hyperlipoproteinemia, serum concentrations of apoprotein B usually decrease during gemfibrozil therapy; decreases in apoprotein B follow changes in LDL-cholesterol. However, in another study in patients with primary hypertriglyceridemia associated with coronary heart disease (CHD), LDL-apoprotein B increased in a few patients. In patients with type V hyperlipoproteinemia, apoprotein B concentration has been reported to increase during gemfibrozil therapy.

In humans, gemfibrozil inhibits lipolysis of fat in adipose tissue and decreases the hepatic uptake of plasma free fatty acids (i.e., free fatty acid turnover is decreased), thereby reducing hepatic triglyceride production (triglyceride turnover rate is decreased). The drug also reportedly inhibits production and increases clearance of VLDL-apoprotein B (VLDL-apoB), leading to a decrease in VLDL-triglyceride production, enhanced clearance of VLDL-triglyceride, and, subsequently, a decrease in serum triglyceride concentrations. The increase in serum total LDL concentration that may occur with gemfibrozil may be caused by a decrease in the catabolic rate of LDL, possibly secondary to an effect(s) of the drug on hepatic metabolism of LDL, and/or by an increase in the catabolic rate of VLDL-cholesterol. In animals, gemfibrozil reduces incorporation of long-chain fatty acids into newly formed triglycerides and inhibits basal, norepinephrine-induced, isoproterenol-stimulated, and cyclic adenosine-3',5'-monophosphate (AMP)-stimulated lipolysis of adipose tissue. It has been proposed that this reduction in adipose tissue lipolysis may be a mechanism for decreased serum triglyceride concentrations; however, it is unlikely that the drug's antilipemic effect in humans results from this mechanism of action.

Gemfibrozil has a plasma half-life of 1.5 hours. In patients with renal failure the half life is 2.4h and in patients with liver disease the half life is 2.1h.

The elimination half-life of gemfibrozil is about 1.5 hours after a single dose and 1.3-1.5 hours after multiple doses in individuals with normal renal function.

The disposition of the lipid-lowering drug gemfibrozil was studied in patients with either renal (n = 8) or hepatic disease (n = 8) and compared to those of healthy volunteers (n = 6). ... Following oral administration of 900 mg gemfibrozil ... the elimination half-life of the drug was 1.5 hr in controls, 2.4 hr in renal failure, and 2.1 hr in liver disease.

Gemfibrozil undergoes hydroxylation at the 5'-methyl and 4' positions to form the M1 and M2 metaolites respectively. Gemfibrozil also undergoes O-glucuronidation to form gemfibrozil 1-beta glucuronide, an inhibitor of CYP2C8. This O-glucuronidation is primarily mediated by UGT2B7, but also by UGT1A1, UGT1A3, UGT1A9, UGT2B4, UGT2B17.

Gemfibrozil is biotransformed extensively following oral administration. A major pathway of gemfibrozil metabolism is via glucuronidation. Following a single oral administration of 450 mg (6 mg/kg bw est) gemfibrozil to six male subjects, gemfibrozil glucuronide represented approximately 50% of the total urinary metabolites (32% of the dose) recovered within 24 hr. Very similar results had been obtained in /another/ ... study, in which 31% of the dose was recovered as urinary gemfibrozil glucuronide over 0-48 hr. Among metabolites resulting from phase I biotransformation, 5-(5-carboxy-2-methylphenoxy)-2,2-dimethyl pentanoic acid (M3) was the major metabolite recovered. ... A 24-hr urine collection contained both free and conjugated M3 at approximately 15% and 5% of the total dose, respectively, while, in /another/ study, free and conjugated M3 represented approximately 7% and 5% of the recovered radiactivity, respectively. Other minor metabolites identified were the 5-hydroxymethyl derivative (M2, an intermediate in the pathway to M3), a 4-hydroxy derivative (M1) and a 2- hydroxymethyl derivative (M4). In aggregate, urinary and fecal excretion of radioactivity accounted for 66% and 6%, respectively, of the elimination of orally administered gemfibrozil over five days.

The exact metabolic fate of gemfibrozil has not been fully elucidated, but the drug appears to be metabolized in the liver to 4 major metabolites produced via 3 metabolic pathways. Gemfibrozil undergoes hydroxylation of the m-methyl group to the corresponding benzyl alcohol derivative (metabolite II), which is rapidly oxidized to a benzoic acid metabolite (metabolite III, 3-[(4-carboxy-4-methylpentyl)oxy]-4-methylbenzoic acid), the major metabolite. The drug also undergoes hydroxylation of the aromatic ring to produce a phenol derivative (metabolite I) which is probably further metabolized to a compound that is phenolic but has no intact carboxylic acid function (metabolite IV). Metabolite I is pharmacologically active. The drug and its metabolites also undergo conjugation.

The roles of multidrug resistance-associated protein (Mrp) 2 deficiency and Mrp3 up-regulation were evaluated on the metabolism and disposition of gemfibrozil. Results from in vitro studies in microsomes showed that the hepatic intrinsic clearance (CLint) for the oxidative metabolism of gemfibrozil was slightly higher (1.5-fold) in male TR- rats, which are deficient in Mrp2, than in wild-type Wistar rats, whereas CLint for glucuronidation was similar in both strains. The biliary excretion of intravenously administered [14C]gemfibrozil was significantly impaired in TR-) rats compared with Wistar rats (22 versus 93% of the dose excreted as the acyl glucuronides over 72 h). Additionally, the extent of urinary excretion of radioactivity was much higher in TR- than in Wistar rats (78 versus 2.6% of the dose). There were complex time-dependent changes in the total radioactivity levels and metabolite profiles in plasma, liver and kidney, some of which appeared to be related to the up-regulation of Mrp3. Overall, it was demonstrated that alterations in the expression of the transporters Mrp2 and Mrp3 significantly affected the excretion as well as the secondary metabolism and distribution of (14)Cgemfibrozil.

... (14)C-Gemfibrozil was administered orally to rats at a dose of 2000 mg/kg. At various time points, radioactivity in urine was analyzed by liquid scintillation spectrometry, high-pressure liquid chromatography, liquid chromatography/mass spectrometry, gas chromatography/mass spectroscopy, and nuclear magnetic resonance. Nine metabolites of gemfibrozil were identified, some that have not been reported previously. Although the majority of metabolites were glucuronidated, some nonglucuronidated metabolites were identified in urine, including a diol metabolite (both ring methyls hydroxylated), and the product of its further metabolism, the acid-alcohol derivative (ortho ring methyl hydroxylated, meta ring methyl completely oxidized to the acid). Hydroxylation of the aromatic ring also was a common pathway for gemfibrozil metabolism, leading to the production of two phenolic metabolites, only one of which was detected in the urine in the nonconjugated or free form. Also of interest was the finding that both acyl and ether glucuronides were produced, including both glucuronide forms of the same metabolite (e. g., 1-O-GlcUA, 5'-COOH-gemfibrozil, and 5'-COO-GlcUA-gemfibrozil); the positions and functionality of the glucuronide conjugates were identified using base hydrolysis or glucuronidase treatment, in combination with liquid chromatography/MS and nuclear magnetic resonance.

Gemfibrozil has known human metabolites that include (2S,3S,4S,5R)-6-[5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoyl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid.

Q8X02027X3

GEMFIBROZIL

Established Pharmacologic Class [EPC] - Peroxisome Proliferator Receptor alpha Agonist

Mechanisms of Action [MoA] - Peroxisome Proliferator-activated Receptor alpha Agonists

Chemical Structure [CS] - Fibric Acids

Gemfibrozil is a Peroxisome Proliferator Receptor alpha Agonist. The mechanism of action of gemfibrozil is as a Peroxisome Proliferator-activated Receptor alpha Agonist.

Substances that lower the levels of certain LIPIDS in the BLOOD. They are used to treat HYPERLIPIDEMIAS.

Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP2C8.

Gemfibrozil is absorbed from the gastrointestinal tract. In healthy volunteers, a 900mg oral dose of gemfibrozil has a Cmax of 46±16µg/mL with a Tmax of 2.2±1.1h. In patients with chronic renal failure, gemfibrozil has a Cmax of 13.8±11.1µg/mL with a Tmax of 2.3±1.0h. In patients with liver disease, gemfibrozil has a Cmax of 23.0±10.3µg/mL with a Tmax of 2.6±1.7h.

Approximately 70% of a dose of gemfibrozil is eliminated in the urine. The majority of a dose is eliminated as a glucuronide conjugate and <2% is elimiinated as the unmetabolized drug. 6% of a dose is eliminated in the feces. In healthy volunteers, 0.02-0.15% of a dose was detected in the urine as unmetabolized gemfibrozil, with 7-14% detected as conjugated metabolites. In patients with renal failure, trace amounts of unmetabolized gemfibrozil is present in the urine, with 0.5-9.8% detected as conjugated metabolites. In patients with liver disease, 0.1-0.2% of a dose was detected in the urine as unmetabolized gemfibrozil, with 25-50% detected as conjugated metabolites.

The volume of distribution of gemfibrozil is estimated to be 0.8L/kg.

The clearance of gemfibrozil is estimated to be 6.0L/h.

Studies in monkeys indicate that gemfibrozil crosses the placenta.

About 95% of gemfibrozil is protein bound. In vitro at concentrations of 0.1-12 ug/mL, 97% of gemfibrozil is bound to 4% human serum albumin; the major metabolite of gemfibrozil (metabolite III) has no effect on the binding capacity of gemfibrozil.

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).