Gemfibrozil treatment significantly reduces (2-3-fold) the plasma clearance of SVA and the biliary excretion of SVA glucuronide (together with its cyclization product SV), but not the excretion of a major oxidative metabolite of SVA in dogs.

Absorption, Distribution and Excretion
Gemfibrozil is absorbed via the gastrointestinal tract. In healthy volunteers, after oral administration of 900 mg gemfibrozil, the peak plasma concentration (Cmax) was 46 ± 16 µg/mL, and the time to peak concentration (Tmax) was 2.2 ± 1.1 h. In patients with chronic renal failure, the peak plasma concentration (Cmax) was 13.8 ± 11.1 µg/mL, and the time to peak concentration (Tmax) was 2.3 ± 1.0 h. In patients with liver disease, the peak plasma concentration (Cmax) was 23.0 ± 10.3 µg/mL, and the time to peak concentration (Tmax) was 2.6 ± 1.7 h. Approximately 70% of the gemfibrozil dose is excreted in the urine. The majority of the dose is excreted as glucuronide conjugates, with less than 2% excreted as unmetabolized drug. 6% of the dose is excreted in the feces. In healthy volunteers, 0.02%–0.15% of the dose was detected in urine as unmetabolized gemfibrozil, and 7%–14% as conjugated metabolites. In patients with renal failure, trace amounts of unmetabolized gemfibrozil were present in urine, with 0.5%–9.8% as conjugated metabolites. In patients with liver disease, 0.1%–0.2% of the dose was detected in urine as unmetabolized gemfibrozil, and 25%–50% as conjugated metabolites. The estimated volume of distribution of gemfibrozil is 0.8 L/kg. The estimated clearance of gemfibrozil is 6.0 L/h. Monkey studies have shown that gemfibrozil crosses the placenta. Approximately 95% of gemfibrozil is bound to proteins. In vitro studies showed that 97% of gemfibrozil bound to 4% of human serum albumin at concentrations of 0.1–12 μg/mL; the major metabolite of gemfibrozil (metabolite III) had no effect on its binding capacity. In animal studies, maximum tissue concentrations of gemfibrozil were reached 1 hour after a single dose, with the highest concentrations in the liver and kidneys. Gemfibrozil is rapidly and completely absorbed from the gastrointestinal tract. The relative bioavailability of gemfibrozil capsules is 97% compared to oral solutions. The drug circulates enterohepaticly. Plasma gemfibrozil concentrations exhibit significant individual variability but generally increase proportionally with increasing dose. Plasma drug concentrations do not appear to be independent of therapeutic response. Peak plasma drug concentrations occur within 1–2 hours after a single or multiple oral doses of gemfibrozil. In one study, the mean peak plasma gemfibrozil concentration was 33 μg/mL in healthy adults after a single oral dose of 800 mg gemfibrozil, occurring 1–2 hours after administration. In another study, healthy adults received multiple oral doses of the drug (600 mg twice daily), with mean peak plasma concentrations of 16–23 μg/mL, occurring approximately 1–2 hours after administration. For more complete data on the absorption, distribution, and excretion of gemfibrozil (9 studies), please visit the HSDB records page.
Metabolism/Metabolites
Gemfibrozil undergoes hydroxylation at the 5'-methyl and 4' positions to form metabolites M1 and M2, respectively. Gemfibrozil also undergoes O-glucuronidation to form gemfibrozil 1-β-glucuronide, an inhibitor of CYP2C8. This O-glucuronidation is primarily mediated by UGT2B7, but also by UGT1A1, UGT1A3, UGT1A9, UGT2B4, and UGT2B17.
Extensive biotransformation occurs after oral administration of gemfibrozil. One of the main metabolic pathways of gemfibrozil is glucuronidation. In six male subjects, following a single oral dose of 450 mg (estimated to be 6 mg/kg body weight) of gemfibrozil, approximately 50% of the metabolites recovered in urine within 24 hours were gemfibrozil glucuronide (32% of the administered dose). Another study yielded very similar results, in which 31% of the administered dose was recovered in urine within 0–48 hours. Among the metabolites generated during Phase I biotransformation, 5-(5-carboxy-2-methylphenoxy)-2,2-dimethylvaleric acid (M3) was the major recovered metabolite. …24-hour urine collection results showed that free and bound M3 accounted for approximately 15% and 5% of the total dose, respectively; while in another study, free and bound M3 accounted for approximately 7% and 5% of the recovered radioactive material, respectively. Other identified minor metabolites include a 5-hydroxymethyl derivative (an intermediate in the M2 and M3 metabolic pathways), a 4-hydroxy derivative (M1), and a 2-hydroxymethyl derivative (M4). Overall, within five days of oral gemfibrozil administration, 66% and 6% of the radioactive material were excreted in urine and feces, respectively. The exact metabolic pathway of gemfibrozil is not fully elucidated, but the drug appears to be metabolized in the liver into four major metabolites, produced via three metabolic pathways. The meta-methyl hydroxylation of gemfibrozil yields the corresponding benzyl alcohol derivative (metabolite II), which is rapidly oxidized to the benzoic acid metabolite (metabolite III, 3-[(4-carboxy-4-methylpentyl)oxy]-4-methylbenzoic acid), the major metabolite. The aromatic ring of the drug also undergoes hydroxylation to generate a phenolic derivative (metabolite I), which may be further metabolized into a phenolic compound, but with an incomplete carboxylic acid group (metabolite IV). Metabolite I is pharmacologically active. The drug and its metabolites also undergo conjugation reactions. This study evaluated the effects of multidrug resistance-associated protein (Mrp) 2 deficiency and Mrp3 upregulation on gemfibrozil metabolism and distribution. In vitro microsomal studies showed that the intrinsic clearance (CLint) of hepatic oxidative metabolism in Mrp2-deficient male TR- rats was slightly higher than that in wild-type Wistar rats (1.5-fold), while glucuronidated CLint was similar in both strains. Compared to Wistar rats, intravenous administration of [14C] gemfibrozil to TR- rats significantly impaired bile excretion (22% of the dose excreted as acyl glucuronide in TR- rats within 72 hours, compared to 93% in Wistar rats). Furthermore, urinary radioactive excretion in TR rats was significantly higher than in Wistar rats (78% and 2.6% of the dose, respectively). Total radioactivity levels and metabolite profiles in plasma, liver, and kidneys exhibited complex time-varying characteristics, some of which appeared to be associated with Mrp3 upregulation. Overall, the study showed that alterations in the expression of transport proteins Mrp2 and Mrp3 significantly affected the excretion, secondary metabolism, and distribution of (14)C-gemfibrozil. ...(14)C-gemfibrozil was orally administered to rats at a dose of 2000 mg/kg. Radioactivity in urine was analyzed at different time points using liquid scintillation counting, high-performance liquid chromatography, liquid chromatography/mass spectrometry, gas chromatography/mass spectrometry, and nuclear magnetic resonance. Nine gemfibrozil metabolites were identified, some of which were previously unreported. Although most metabolites were present in glucuronidated form, some non-glucuronidated metabolites were also detected in urine, including a diol metabolite (both cyclic methyl groups were hydroxylated) and its further metabolites—an acid-alcohol derivative (the ortho-cyclic methyl group was hydroxylated, and the meta-cyclic methyl group was completely oxidized to an acid). Hydroxylation of the aromatic ring was also a common pathway in gemfibrozil metabolism, resulting in the formation of two phenolic metabolites, only one of which was detected in urine in an unbound or free form. Furthermore, it is noteworthy that acyl and ether glucuronides are also generated, including two glucuronide forms of the same metabolite (e.g., 1-O-GlcUA, 5'-COOH-gefitrazil, and 5'-COO-GlcUA-gefitrazil). The location and function of the glucuronide conjugates were identified using alkaline hydrolysis or glucuronidase treatment combined with liquid chromatography/mass spectrometry and nuclear magnetic resonance. Known metabolites of gemfibrozil include (2S,3S,4S,5R)-6-[5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl]oxy-3,4,5-trihydroxyoxacyclohexane-2-carboxylic acid. Hepatic metabolism: Gefitrazil is primarily excreted via the oxidation of the cyclic methyl group, sequentially generating hydroxymethyl and carboxyl metabolites. Elimination pathway: Approximately 70% of the administered dose is excreted in the urine, primarily as glucuronide conjugates, with less than 2% excreted unchanged gemfibrozil.
Half-life: 1.5 hours

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Biological Half-life
The plasma half-life of gemfibrozil is 1.5 hours. The half-life in patients with renal failure is 2.4 hours, and in patients with liver disease is 2.1 hours.
The elimination half-life after a single dose of gemfibrozil in individuals with normal renal function is approximately 1.5 hours, and after multiple doses, it is approximately 1.3-1.5 hours.
This study investigated the distribution of the lipid-lowering drug gemfibrozil in patients with renal disease (n = 8) and patients with liver disease (n = 8), and compared it with healthy volunteers (n = 6). …After oral administration of 900 mg gemfibrozil…the elimination half-life was 1.5 hours in the control group, 2.4 hours in the renal failure group, and 2.1 hours in the liver disease group.

Toxicity Summary
Gemfibrozil increases the activity of extrahepatic lipoprotein lipase (LL), thereby promoting the breakdown of lipoprotein triglycerides. Its mechanism of action is through activation of the peroxisome proliferator-activated receptor α (PPARα) transcription factor ligand, which is involved in carbohydrate and fat metabolism and adipose tissue differentiation. Increased lipoprotein lipase synthesis further promotes triglyceride clearance. Chylomicrons are degraded, very low-density lipoprotein (VLDL) is converted to low-density lipoprotein (LDL), and LDL is converted to high-density lipoprotein (HDL). Simultaneously, the secretion of lipids in bile and the final intestine is slightly increased. Gemfibrozil also inhibits the synthesis of apolipoprotein B (a carrier molecule of VLDL) and promotes its clearance. Hepatotoxicity
Approximately 20% of patients taking gemfibrozil experience mild, transient elevations in serum transaminases, but only 5% or fewer experience elevations more than three times the normal value. These abnormalities are usually asymptomatic and transient, and resolve spontaneously with continued use. However, there have been a few reports of clinically significant liver injury in patients taking gemfibrozil long-term. Clinical presentations vary considerably. The onset of injury ranges from weeks to years after starting medication, and the pattern of elevated serum enzymes varies from hepatocellular (Case 1) to mixed and cholestatic. No symptoms of immune-mediated hepatitis (fever, rash, eosinophilia) or autoimmune hepatitis were observed in the cases, and rapid and complete recovery occurred after discontinuation of the drug.
Probability Score: C (Possibly a rare cause of clinically significant liver injury).

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Effects during Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no published information regarding the use of gemfibrozil during lactation. Due to concerns about potential disruption of lipid metabolism in infants, it is best to avoid using gemfibrozil during lactation. Especially in breastfeeding newborns or premature infants, other medications should be preferred.
◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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Protein Binding
Germebazole has a protein binding rate of 99%. Of this, 98.6% is bound to serum albumin, 0.8% to erythrocytes, and 0.8% exists in free form. Binding to α-1-acid glycoprotein is negligible.

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Toxicity Data
Oral administration in mice: LD50 = 3162 mg/kg.

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Interactions
In a randomized crossover study, 24 healthy volunteers genotyped by SLCO181 received 1200 mg gemfibrozil, 40 mg atorvastatin, or placebo daily, with 0.25 mg repaglinide on day 3. The mean increase in the area under the plasma concentration-time curve (AUC_0-∞) of repaglinide induced by gemfibrozil was greater in individuals with the SLCO1B1 c.521CC genotype (n = 6) than in individuals with the c.521TC genotype (n = 6) and the c.521TT genotype (n = 6).¹² The genotype effect was 1.56-fold (P = 0.004) and 1.54-fold (P = 0.002), respectively. Gemfibrozil prolonged the elimination half-life of repaglinide by 1.43-fold (P = 0.047) in the c.521CC group, but had no difference in effect on peak plasma concentration (Cmax). During gemfibrozil administration, the lowest blood glucose concentration after repaglinide administration in c.521CC subjects was 19% lower than that in c.521TT subjects (P = 0.009). In the c.521TT group, atorvastatin administration increased repaglinide's Cmax and AUC(0-∞) by 41% (P = 0.001) and 18% (P = 0.033), respectively. In summary, the extent of the interaction between gemfibrozil and repaglinide depends on the SLCO1B1 genotype. Atorvastatin can increase plasma repaglinide concentrations, possibly by inhibiting organic anion transport peptide 1B1 (OATP1B1). ...In a randomized crossover study, 12 healthy volunteers received 600 mg gemfibrozil, 100 mg itraconazole (initial dose 200 mg), gemfibrozil plus itraconazole, or placebo twice daily for 3 consecutive days. On day 3, they received 0.25 mg repaglinide. Plasma drug and blood glucose concentrations were monitored within 7 hours of administration, and serum insulin and C-peptide concentrations were monitored within 3 hours of administration. Gemfibrozil increased the area under the plasma concentration-time curve (AUC) of repaglinide by 8.1-fold (range 5.5 to 15.0-fold; p < 0.001) and prolonged its half-life (t_1/2) from 1.3 hours to 3.7 hours (p < 0.001). While itraconazole monotherapy only increased repaglinide's AUC by 1.4-fold (1.1 to 1.9-fold; p < 0.001), the combination of gemfibrozil and itraconazole increased its AUC by 19.4-fold (12.9 to 24.7-fold) and prolonged repaglinide's t_1/2 to 6.1 hours (p < 0.001). Gemfibrozil increased repaglinide plasma concentration by 28.6-fold at 7 hours, while the combination of gemfibrozil and itraconazole increased repaglinide plasma concentration by 70.4-fold (p<0.001). Gemfibrozil monotherapy or combination therapy with itraconazole significantly enhanced and prolonged the hypoglycemic effect of repaglinide; in other words, repaglinide becomes a long-acting and more potent hypoglycemic agent. Clinicians should be aware of this previously undiscovered and potentially dangerous interaction between gemfibrozil and repaglinide. It is best to avoid concurrent use of gemfibrozil and repaglinide. If combination therapy is deemed necessary, the repaglinide dose should be significantly reduced, and blood glucose levels should be closely monitored. In healthy subjects receiving gemfibrozil 600 mg twice daily for 3 consecutive days, concomitant administration of gemfibrozil 600 mg and a single dose of 0.25 mg repaglinide (a dosage not yet marketed in the US) increased repaglinide's AUC by 8.1-fold and prolonged its half-life from 1.3 hours to 3.7 hours. When both gemfibrozil and itraconazole were used in combination with repaglinide, repaglinide's AUC increased by 19-fold and its half-life prolonged to 6.1 hours. Concomitant administration of gemfibrozil increased plasma repaglinide concentration by 28.6-fold at 7 hours; concomitant administration of gemfibrozil and itraconazole increased plasma repaglinide concentration by 70.4-fold. Patients taking repaglinide should not start taking gemfibrozil, and patients taking gemfibrozil should not start taking repaglinide, as such concomitant use may enhance and prolong repaglinide's hypoglycemic effect. Furthermore, due to the significant synergistic inhibitory effect of gemfibrozil and itraconazole on repaglinide metabolism, patients already receiving combination therapy with repaglinide and gemfibrozil should not take itraconazole.
Myopathy and/or fatal or non-fatal rhabdomyolysis have been reported with combination therapy with gemfibrozil and statins (e.g., cerivastatin [discontinued], lovastatin).
For more complete data on drug interactions with gemfibrozil (15 items in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 479 mg/kg
Oral LD50 in mice: 316 mg/kg

J Pharmacol Exp Ther.2002 Jun;301(3):1042-51;Drug Metab Dispos.2001 Nov;29(11):1359-61.

Therapeutic Uses
Gemfibrozil is used to reduce the risk of coronary artery disease in patients with type IIb hyperlipoproteinemia who have no clinical evidence of coronary artery disease (primary prevention) and who have an inadequate response to diet management, weight loss, exercise, and medications known to lower LDL cholesterol and raise HDL cholesterol (e.g., bile acid sequestrants), and who also have low HDL cholesterol levels in addition to elevated LDL cholesterol and triglycerides. /US product label includes/
In a randomized, double-blind, five-year trial, researchers investigated the efficacy of gemfibrozil in simultaneously raising serum high-density lipoprotein (HDL) cholesterol levels and lowering non-HDL cholesterol levels, thereby reducing the risk of coronary artery disease. The trial enrolled 4081 asymptomatic middle-aged men (40 to 55 years of age) with primary dyslipidemia (non-HDL cholesterol greater than or equal to 200 mg/dL [5.2 mmol/L] in two consecutive measurements prior to treatment. One group (2051 men) received 600 mg gemfibrozil twice daily, while the other group (2030 men) received a placebo. Gemfibrozil significantly increased HDL cholesterol levels and persistently decreased serum total cholesterol, LDL cholesterol, non-HDL cholesterol, and triglyceride levels. Lipid levels changed minimally in the placebo group. The cumulative cardiac endpoint event rate at five years was 27.3 per 1000 individuals in the gemfibrozil group and 41.4 per 1000 individuals in the placebo group—a 34.0% reduction in coronary heart disease incidence (95% confidence interval, 8.2% to 52.6%; P < 0.02; two-tailed test). The incidence reduction began to appear in the second year in the gemfibrozil group and persisted until the end of the study. There was no difference in overall mortality between the two groups, and the treatment did not affect cancer incidence. ...To compare the efficacy and safety of lipid-lowering therapy in HIV-infected and non-HIV-infected individuals, we conducted a retrospective cohort study that included 829 HIV-infected and 6941 non-HIV-infected individuals who had started lipid-lowering therapy due to elevated LDL cholesterol or triglyceride levels. Compared with HIV-free patients, HIV-infected patients starting statin therapy experienced a smaller decrease in LDL cholesterol levels (25.6% vs. 28.3%; P = 0.001), and this decrease was independent of the type of antiretroviral therapy. The decrease in triglyceride levels in HIV-infected patients starting gemfibrozil treatment was significantly less than in HIV-uninfected patients (44.2% vs. 59.3%; P < 0.001), and the decrease in triglyceride levels after gemfibrozil treatment varied by antiretroviral therapy type (44.0% in patients receiving protease inhibitors only [P = 0.001], 26.4% in patients receiving protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs) [P < 0.001], and 60.3% in patients receiving NNRTIs only [P = 0.94]). Three HIV-infected patients and one non-HIV-infected patient were diagnosed with rhabdomyolysis. No clinically confirmed cases of myositis or myopathy were observed. The risk of laboratory adverse events was low (<5%), but higher in HIV-infected patients. Limitations: Laboratory testing was not standardized according to HIV infection status, and adequate fasting before lipoprotein testing could not be verified. The findings may not be entirely applicable to uninsured individuals, women, or certain racial or ethnic groups. Dyslipidemia, particularly hypertriglyceridemia, is more difficult to treat in HIV-infected patients compared to the general population. However, triglyceride responses in HIV-infected patients receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy and gemfibrozil were similar to those in HIV-uninfected patients. Gemfibrozil can be used as an adjunct to diet therapy for patients with severe hypertriglyceridemia at risk of pancreatitis (typically defined as those with serum triglyceride concentrations exceeding 2000 mg/dL and elevated very low-density lipoprotein (VLDL) and fasting chylomicron concentrations who do not respond well to dietary therapy. Gemfibrozil can also be used in patients with triglyceride levels of 1000-2000 mg/dL and a history of pancreatitis or recurrent episodes of typical abdominal pain associated with pancreatitis; however, its efficacy in patients with type V hyperlipoproteinemia (type V hyperlipoproteinemia) and triglyceride levels below 1000 mg/dL due to dietary or alcohol consumption has not been adequately studied. The manufacturer states that gemfibrozil is not indicated for patients with type I hyperlipoproteinemia who have elevated triglyceride and chylomicron levels but normal very low-density lipoprotein cholesterol (VLDL-C) levels. /US product label contains/
For more complete data on the therapeutic uses of gemfibrozil (of 6 types), please visit the HSDB record page.

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Drug Warnings
Adverse reactions to gemfibrozil are uncommon and usually mild; however, due to the chemical, pharmacological, and clinical similarities between gemfibrozil and clofibrate (discontinued in the US), the potential for gemfibrozil to have similar toxicities to clofibrate should be considered. The most common adverse reactions to gemfibrozil involve the gastrointestinal tract and can sometimes be severe enough to require discontinuation of the drug. Common gastrointestinal adverse reactions after taking gemfibrozil include abdominal pain (in some cases even acute appendicitis), upper abdominal pain, or indigestion. Nausea, vomiting, diarrhea, constipation, and flatulence occur less frequently; cholestatic jaundice has also been reported. Patients taking gemfibrozil have also reported symptoms such as dry mouth, anorexia and/or weight loss, flatulence, pancreatitis, colitis, and heartburn, but these symptoms are not directly attributable to the drug. Patients taking gemfibrozil have also reported adverse reactions such as headache, dizziness, drowsiness or sleepiness, blurred vision, paresthesia, hypoesthesia, taste disturbances, peripheral neuritis, depression, and impotence and decreased libido. Although causality has not been established, patients taking this drug have also experienced symptoms such as vertigo, syncope, insomnia, weakness, chills, mental problems, fatigue, confusion, and seizures. A small number of patients taking gemfibrozil have experienced a slight decrease in hemoglobin, hematocrit, and white blood cell count; these indicators tend to stabilize with long-term use. Eosinophilia has also been reported. This drug may also affect blood clotting. Severe anemia, leukopenia, thrombocytopenia, and myelosuppression have been reported in rare cases in patients taking gemfibrozil. Therefore, the manufacturer recommends regular monitoring of blood cell counts during the first 12 months of treatment. For more complete data on drug warnings for gemfibrozil (19 in total), please visit the HSDB records page.
Pharmacodynamics
Gemfibrozil treats patients with hyperlipidemia by altering lipid metabolism. Because gemfibrozil has a long mean residence time of up to 9.6 hours in patients with chronic renal failure, it needs to be administered twice daily to maintain its duration of action. Gemfibrozil has a broad therapeutic index, as no serious side effects were observed in trials using twice the standard dose. Patients taking gemfibrozil may have an increased risk of developing gallstones and cholecystitis, similar to the risk for patients taking clofibrate.

C15H22O3

250.33

250.156

25812-30-0

Gemfibrozil;25812-30-0

3463

White to off-white solid powder

1.0±0.1 g/cm3

394.7±30.0 °C at 760 mmHg

61-63°C

141.6±18.1 °C

0.0±1.0 mmHg at 25°C

1.512

4.39

1

3

6

18

273

0

HEMJJKBWTPKOJG-UHFFFAOYSA-N

InChI=1S/C15H22O3/c1-11-6-7-12(2)13(10-11)18-9-5-8-15(3,4)14(16)17/h6-7,10H,5,8-9H2,1-4H3,(H,16,17)

5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)