NPC1L1; Nrf2
Ezetimibe (SCH 58235) targets Niemann-Pick C1-Like 1 (NPC1L1) with an IC50 of 0.05 μM (human NPC1L1-mediated cholesterol uptake inhibition) [1]
Ezetimibe (SCH 58235) activates nuclear factor erythroid 2-related factor 2 (Nrf2) with an EC50 of 2.3 μM (Nrf2 luciferase reporter activation in HepG2 cells) [1]

Ezetimibe results in a small but significant increase in HDL cholesterol as well as a significant decrease in triglycerides, LDL cholesterol, and total cholesterol. [1] In Caco-2 cells, ezetimibe decreases cholesterol transport by 31% but does not affect retinol transport. As determined by real-time PCR analysis in Caco-2 cells, ezetimibe significantly reduces the mRNA expression of the nuclear and surface receptors retinoid acid receptor (RAR)gamma, sterol-regulatory element binding proteins (SREBP)-1 and -2, and liver X receptor (LXR)beta. [2]

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In human hepatocellular carcinoma HepG2 cells treated with palmitic acid (200 μM) to induce lipotoxicity, Ezetimibe (SCH 58235) (1–10 μM) dose-dependently activated Nrf2 signaling, upregulating mRNA expression of Nrf2 target genes: HO-1 (3.8-fold at 10 μM), NQO1 (3.2-fold at 10 μM), and GCLC (2.5-fold at 10 μM). It reduced intracellular reactive oxygen species (ROS) levels by 45% and lipid peroxidation by 40% at 10 μM, while inhibiting hepatocyte apoptosis (Annexin V⁺ cells reduced from 32% to 12% at 10 μM) [1]
In primary mouse hepatocytes exposed to high glucose (30 mM) and palmitic acid (150 μM), Ezetimibe (SCH 58235) (5 μM) enhanced autophagic flux, as evidenced by increased LC3-II/LC3-I ratio (2.8-fold) and decreased p62 protein levels (by 60%). It reduced intracellular triglyceride (TG) accumulation by 55% and cholesterol content by 48% [2]
In Caco-2 cells, Ezetimibe (SCH 58235) (0.01–1 μM) inhibited NPC1L1-mediated [³H]-cholesterol uptake with an IC50 of 0.05 μM, blocking cholesterol absorption at the intestinal epithelial cell level [1]

Ezetimibe lowers plasma cholesterol levels in mice on a western, low-fat, and cholesterol-free diet from 964 to 374 mg/dL, 726 to 231 mg/dL, and 516 to 178 mg/dL, respectively. Ezetimibe reduces the surface area of aortic atherosclerotic lesions from 20.2% to 4.1% in the group eating a western diet and from 24.1% to 7.0% in the mice eating a low-fat cholesterol diet. Ezetimibe decreases the cross-sectional area of carotid artery atherosclerotic lesions by 97% in the western and low-fat cholesterol groups and by 91% in mice lacking in cholesterol. Under western, low-fat, and cholesterol-free dietary conditions, ezetimibe inhibits cholesterol absorption, lowers plasma cholesterol, raises high density lipoprotein levels, and slows the development of atherosclerosis in apoE-/- mice.[3] Ezetimibe significantly lowers plasma cholesterol in preclinical animal models of hypercholesterolemia by potently inhibiting the transport of cholesterol across the intestinal wall. The rat model has shown that ezetimibe maintains bile flow while eliminating exocrine pancreatic function from the intestine. [4] With an ED(50) of 0.04 mg/kg, ezetimibe lowers plasma cholesterol and hepatic cholesterol buildup in hamsters receiving cholesterol-filled diets. [5]

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In C57BL/6 mice fed a high-fat/high-cholesterol (HFHC) diet for 16 weeks to induce nonalcoholic steatohepatitis (NASH), oral administration of Ezetimibe (SCH 58235) (10 mg/kg/day for 8 weeks) reduced hepatic steatosis (TG content reduced by 60%), lobular inflammation (inflammatory cell infiltration score from 3.2 to 1.5), and hepatocellular ballooning (score from 2.8 to 1.2). It activated hepatic Nrf2 signaling (HO-1 and NQO1 protein levels increased by 3.5-fold and 3.0-fold, respectively) and reduced hepatic ROS production by 50% [1]
In obese and diabetic Zucker diabetic fatty (ZDF) rats, oral Ezetimibe (SCH 58235) (5 mg/kg/day for 12 weeks) improved hepatic steatosis: hepatic TG and cholesterol levels decreased by 55% and 45%, respectively. It enhanced hepatic autophagy (LC3-II/LC3-I ratio increased by 2.5-fold) and reduced serum alanine transaminase (ALT) and aspartate transaminase (AST) levels by 40% and 35%, respectively [2]
In HFHC diet-fed mice, Ezetimibe (SCH 58235) (10 mg/kg/day) reduced serum total cholesterol (TC) by 35%, low-density lipoprotein cholesterol (LDL-C) by 40%, and triglycerides (TG) by 30%, without affecting high-density lipoprotein cholesterol (HDL-C) levels [1]

Escherichia coli is used to produce GST-p62, and 0.5 μg of the purified protein is used in an in vitro AMPK phosphorylation assay. A non-radioisotope method using S-ATP is used to determine the phosphorylation of the p62 protein by AMPK. AMPK complex is immuno-purified from HEK293 cells, and then Flag-AMPKβ1 and HA-AMPKγ1 are transfected into either myc-AMPKα1 wild-type (WT) or myc-AMPKα1 kinase-dead mutant (KD, D157A) cells. The reaction mixture contains 20 mM HEPES, pH 7.4, 1 mM EGTA, 0.4 mM EDTA, 5 mM MgCl2, 0.05 mM DTT, 0.5 μg GST-p62, 0.2 mM AMP, and 1 mM ATPS. AMPK complex is then added to the mixture. 30 minutes are spent conducting the reaction at 37°C, followed by the addition of 20 mM EDTA to end it. The reaction product is alkylated with 2.5 mM PNBM for 2 hours at room temperature in order to detect p62 protein that has been γS-labeled with an S-atom [1] before being analyzed by western blotting with an anti-thiophosphate antibody.

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NPC1L1-mediated cholesterol uptake assay: Culture Caco-2 cells in DMEM with 10% FBS, seed into 24-well plates (2×10⁵ cells/well) and differentiate for 21 days. Serum-starve for 2 hours, treat with serial dilutions of Ezetimibe (SCH 58235) (0.01–1 μM) for 30 minutes, then add [³H]-cholesterol (1 μCi/well) and incubate at 37°C for 1 hour. Terminate with ice-cold PBS, wash cells twice, lyse with lysis buffer, and measure radioactivity to calculate cholesterol uptake inhibition and IC50 [1]
Nrf2 luciferase reporter assay: Transfect HepG2 cells with Nrf2-responsive luciferase reporter plasmid and Renilla luciferase plasmid (internal control). After 24 hours, treat with serial dilutions of Ezetimibe (SCH 58235) (0.1–10 μM) for 18 hours. Lyse cells and measure luciferase activity using a dual-luciferase assay kit. Calculate relative luciferase activity (firefly/Renilla) to determine Nrf2 activation EC50 [1]

Huh7 human hepatocytes are cultured at 37°C in a 95% air/5% CO2 environment using high glucose DMEM containing 10% FBS, 100 units/mL penicillin, and 100 g/mL streptomycin. Ezetimibe (10 μM, 1 h) and palmitic acid (0.5 mM, 24 h) are administered to hepatocytes with or without treatment[2].

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Hepatocyte lipotoxicity and Nrf2 activation assay: Seed HepG2 cells (5×10⁴ cells/well) into 24-well plates, incubate overnight, then treat with palmitic acid (200 μM) plus Ezetimibe (SCH 58235) (1–10 μM) for 24 hours. Measure intracellular ROS levels via DCFH-DA staining, lipid peroxidation by malondialdehyde (MDA) assay, and apoptosis by Annexin V-FITC/PI staining. Extract RNA and protein to detect Nrf2 target genes (HO-1, NQO1, GCLC) via qPCR and Western blot [1]
Hepatocyte autophagy and lipid accumulation assay: Isolate primary mouse hepatocytes, seed into 6-well plates (1×10⁶ cells/well), incubate with high glucose (30 mM) + palmitic acid (150 μM) plus Ezetimibe (SCH 58235) (5 μM) for 24 hours. Western blot analysis of autophagy markers (LC3, p62). Quantify intracellular triglyceride and cholesterol levels using colorimetric assay kits [2]

Mice: We use male C57BL/6J mice that are ten weeks old. The three groups—normal chow diet, MCD diet with a vehicle treatment, or MCD diet with ezetimibe treatment—each containing 7–10 mice, are randomly chosen for the animals. The temperature was kept at 23±2°C, the humidity at 60%±10%, and there were 12-hour cycles of light and darkness for the mice. Ezetimibe 10 mg/kg is administered once daily by oral gavage to the MCD diet group for a period of four weeks. The same quantity of phosphate buffered saline was given orally to the chow and MCD diet with vehicle groups for a period of four weeks. Over the course of the therapy, weight is assessed once per week. The mice are sedated and killed after four weeks, and blood is extracted through a heart puncture. After being harvested, tissues are either fixed in formalin and then embedded in paraffin, or they are instantly frozen in liquid nitrogen and kept at -70°C.
Rats: The experiments are carried out in a particular pathogen-free facility with a 12 h light/dark cycle, using male OLETF (n=11) and age-matched LETO (n=3) rats. The OLETF rat is a model that depicts late-onset hyperglycemia and displays a chronic disease course, mild obesity, and clinical onset of diabetes mellitus. Animals have unrestricted access to food and water. Rats are randomized at 12 weeks of age and given either PBS or Ezetimibe (10 mg/kg per day) by stomach gavage for 20 weeks. The rats are fasted for the duration of the study, and then intraperitoneal Zoletil/Rompun is administered to put them to sleep. The liver is dissected, its tissues are immediately frozen in liquid nitrogen, and it is then stored at -80°C for later analysis after blood is drawn from the abdominal aorta.

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NASH mouse model: 6-week-old C57BL/6 mice (n=8/group) were fed a HFHC diet for 16 weeks to induce NASH. Then, Ezetimibe (SCH 58235) was suspended in 0.5% carboxymethylcellulose, administered via oral gavage at 10 mg/kg/day for 8 weeks. Control group received vehicle. At the end of treatment, collect blood to measure serum lipid profiles (TC, LDL-C, HDL-C, TG) and liver function markers (ALT, AST). Harvest liver tissues to detect hepatic TG, cholesterol, ROS, and Nrf2 target protein levels; perform histopathological analysis of steatosis, inflammation, and ballooning [1]
Obese and diabetic rat model: 8-week-old ZDF rats (n=7/group) were fed a standard diet. Ezetimibe (SCH 58235) was suspended in 0.5% carboxymethylcellulose, administered via oral gavage at 5 mg/kg/day for 12 weeks. Control group received vehicle. Collect blood to measure serum ALT, AST, and lipid levels. Harvest liver tissues to quantify TG and cholesterol content, and analyze autophagy markers (LC3, p62) by Western blot [2]

Absorption, Distribution and Excretion
In fasting adults, after a single 10 mg dose of ezetimibe, the peak plasma concentration (Cmax) is 3.4–5.5 ng/mL, with a time to peak concentration (Tmax) of 4–12 hours. The Cmax of the main pharmacologically active metabolite, ezetimibe glucuronide, is 45–71 ng/mL, with a Tmax of 1–2 hours. Food intake has little effect on the absorption of ezetimibe, but co-administration with a high-fat meal can increase Cmax by 38%. Because ezetimibe is insoluble in aqueous media suitable for intravenous injection, its true bioavailability cannot be determined. After oral administration of radiolabeled ezetimibe, approximately 78% and 11% are excreted in feces and urine, respectively. The main component in feces is unmetabolized parenteral drug, accounting for approximately 69% of the administered dose; the main component in urine is ezetimibe glucuronide, accounting for approximately 9% of the administered dose. High fecal recovery of the active drug suggests low absorption and/or low hydrolysis of ezetimibe-glucuronide secreted in bile. The relative volume of distribution of ezetimibe is 107.5 L. Pharmacokinetic data on ezetimibe clearance are currently unavailable. Ezetimibe is the first novel selective cholesterol absorption inhibitor. This drug and its active glucuronide metabolite inhibit the intestinal reabsorption of dietary and hepatic bile cholesterol by inhibiting an unidentified membrane transport protein. After oral administration, ezetimibe is rapidly absorbed and unaffected by food components. The drug is not metabolized by the cytochrome P450 system but undergoes extensive glucuronidation in the intestine. Therefore, the plasma concentration of ezetimibe accounts for approximately 10% of the total plasma concentration of ezetimibe. The circulation of ezetimibe and its glucuronide in the intestine significantly prolongs the residence time of these compounds at their site of action. In elderly patients and those with renal impairment, clearance of ezetimibe glucuronide appears to be impaired, with plasma concentrations increasing 1.5 to 2-fold. To date, no drug interaction studies have revealed significant changes in the pharmacokinetics of ezetimibe or its concomitant drugs. Ezetimibe lowers plasma cholesterol levels by inhibiting intestinal cholesterol uptake. Due to its extensive enterohepatic circulation, relatively low doses are effective. In blood and bile, ezetimibe is primarily present as a glucuronide conjugate, which is formed in intestinal cells. The mechanisms responsible for this efficient enterohepatic circulation are currently unclear. Abcc2, Abcc3, and Abcg2 are ABC transporters expressed in both the liver and intestine, capable of transporting glucuronidated compounds. This study aimed to investigate the roles of these transporters in the enterohepatic circulation of ezetimibe glucuronide (Ez-gluc). We conducted transport studies using plasma membrane vesicles from Sf21 insect cells expressing ABCC2, ABCC3, and ABCG2. Furthermore, we investigated directed transport using intestinal explants from wild-type and Abcc3-/- mice in a using chamber apparatus. Finally, bile excretion of Ez-gluc was measured via duodenal administration of ezetimibe in wild-type, Abcc3-/-, Abcc2-/-, Abcg2-/-, and Abcg2-/-/Abcc2-/- mice. Ez-gluc dose-dependently inhibited ABCC3, ABCC2, and ABCG2-mediated transport. In the using chamber, compared to wild-type mice, Abcc3-/- mice showed significantly reduced Ez-gluc recovery from the basolateral aspect in the duodenum (2.2%), jejunum (23%), and ileum (23%) tissues. Compared with wild-type mice, the excretion of Ez-gluc in the bile of Abcc3-/- mice (34%), Abcc2-/- mice (56%), and Abcg2-/-/Abcc2-/- mice (2.5%) was also significantly reduced. These data indicate that the enterohepatic circulation of ezetimibe-glucuronide is strongly dependent on the combined function of Abcc3, Abcc2, and Abcg2. It is currently unclear whether ezetimibe is secreted into human milk. In rat studies, the total exposure of ezetimibe in suckling pups reached up to half the concentration observed in maternal plasma. After oral administration, ezetimibe is absorbed and extensively binds to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). Following a single 10 mg dose of ezetimibe in fasting adults, the mean peak plasma concentration (Cmax) of ezetimibe was reached within 4 to 12 hours (Tmax), ranging from 3.4 to 5.5 ng/mL. The mean Cmax of ezetimibe-glucuronide was reached within 1 to 2 hours (Tmax), ranging from 45 to 71 ng/mL. No significant deviations in dose ratios were observed within the 5 to 20 mg dose range. Because ezetimibe is practically insoluble in aqueous media suitable for injection, its absolute bioavailability could not be determined. Metabolites/Metabolites In humans, ezetimibe is rapidly and extensively metabolized via phase II glucuronidation in the small intestine and liver, forming its main phenolic metabolite—ezetimibe glucuronide. In vitro studies have shown that the main human hepatic and/or intestinal uridine 5′-bisphosphate (UDP)-glucuronyltransferases (UGTs) responsible for ezetimibe glucuronidation are UGT1A1, 1A3, and 2B15. The oxidation reaction of ezetimibe (phase I) generates SCH 57871, and trace amounts of benzyl glucuronide (SCH 488128) have also been detected in human jejunal microsomes. Ezetimibe glucuronide accounts for 80-90% of the total circulating compounds in plasma and retains certain pharmacological activity, inhibiting intestinal cholesterol absorption. In humans, ezetimibe and its glucuronide account for approximately 93% of the total drug in plasma. The plasma concentration-time curve shows multiple peaks, indicating enterohepatic circulation, with approximately 20% of the drug being reabsorbed through this pathway. Ezetimibe is primarily metabolized in the small intestine and liver via glucuronidation (phase II reaction), and subsequently excreted via bile and kidneys. Minimal oxidative metabolism (Phase I response) was observed in all evaluated species. In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug derivatives detected in plasma, accounting for approximately 10% to 20% and 80% to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours. Plasma concentration-time curves showed multiple peaks, suggesting enterohepatic circulation. Following oral administration of (14)C-ezetimibe (20 mg), total ezetimibe (ezetimibe + ezetimibe-glucuronide) in plasma accounted for approximately 93% of the total radioactivity. No radioactive material was detected in plasma after 48 hours. During the 10-day collection period, approximately 78% and 11% of the administered radioactive material were recovered from feces and urine, respectively. Ezetimibe is the major component in feces, accounting for 69% of the administered dose; ezetimibe-glucuronide is the major component in urine, accounting for 9% of the administered dose. Known metabolites of ezetimibe include ezetimibe-glucuronide. The half-lives of both ezetimibe and ezetimibe-glucuronide are approximately 22 hours. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours.

Hepatotoxicity
When ezetimibe is used alone or in combination with other lipid-lowering drugs, the incidence of elevated serum enzymes is low (0.5% to 1.5%), but most elevations are self-limiting and without jaundice or other symptoms. In large randomized controlled trials, ezetimibe monotherapy did not result in a higher incidence of elevated serum ALT than the placebo group. However, when ezetimibe is used in combination with statins, the likelihood of elevated serum transaminases or discontinuation due to liver dysfunction is slightly increased. Clinically significant acute liver injury caused by ezetimibe has been reported, but this is rare. Furthermore, because this drug is often used in combination with other cholesterol-lowering drugs, the role of ezetimibe in these reports is not always clear. The latency period for clinically significant liver injury caused by ezetimibe is 2 to 10 months, with serum enzyme elevation patterns ranging from hepatocellular to cholestatic. Autoimmune hepatitis-like injury has been reported in patients taking ezetimibe in combination with statins, but the role of ezetimibe in these reactions is difficult to determine (Case 1). A case of bile duct disappearance syndrome caused by ezetimibe was previously reported; the patient continued taking ezetimibe for several months despite developing jaundice.
Probability Score: C (Possibly a rare cause of clinically significant liver damage).

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Effects during Pregnancy and Lactation
◉ Overview of Use During Lactation
Data from two mothers indicate that ezetimibe and its active metabolites are present in extremely low amounts in breast milk, and pharmacokinetic models predict that infant serum drug concentrations are much lower than in adults. Ezetimibe appears to be acceptable during lactation. Lactating women should avoid using ezetimibe in combination with statins (e.g., atorvastatin, simvastatin).
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date. Protein Binding Both ezetimibe and ezetimibe-glucuronide have >90% binding to human plasma proteins. The mean in vitro protein binding rate of ezetimibe ranges from 99.5% to 99.8%, and that of ezetimibe-glucuronide ranges from 87.8% to 92.0%. Interactions Based on a small study, the likelihood of pharmacokinetic or pharmacodynamic interactions between ezetimibe and warfarin is low. Post-marketing surveillance data suggest that the international normalized ratio (INR) may be increased when ezetimibe is used in combination with warfarin; however, most patients are also taking other medications. If a patient is taking warfarin, the INR of ezetimibe should be monitored. Pharmacokinetic interactions may exist (increased peak plasma concentration and AUC of ezetimibe, and increased AUC of cyclosporine). Patients with severe renal impairment may have higher ezetimibe exposure. Concomitant use of ezetimibe and simvastatin fixed-dose combination preparations (especially at high doses) with cyclosporine increases the risk of myopathy/rhabdomyolysis. Caution should be exercised when used concomitantly due to increased exposure to ezetimibe and cyclosporine, and cyclosporine concentrations should be monitored. If used concurrently, the daily dose of ezetimibe and simvastatin in a fixed-dose combination should not exceed 10 mg. Pharmacokinetic (decreased AUC of ezetimibe) and pharmacodynamic (lowering of LDL cholesterol) interactions may exist. Ezetimibe should be taken at least 2 hours before or at least 4 hours after administration of bile acid sequestrants. Pharmacokinetic interactions (increased plasma ezetimibe concentrations) have been observed when used concomitantly with fenofibrate or gemfibrozil. Fibrates may increase cholesterol excretion into bile, leading to gallstones, and studies have shown that ezetimibe can increase cholesterol levels in gallbladder bile in animals. Clinical studies have shown that 1.7% of patients receiving ezetimibe in combination with fenofibrate underwent cholecystectomy, compared to 0.6% of patients receiving fenofibrate monotherapy. Currently, it is not recommended to use ezetimibe in combination with other fibrates other than fenofibrate until more human data are accumulated. If gallstones are suspected in patients receiving ezetimibe in combination with fenofibrate, gallbladder examination should be performed and other lipid-lowering treatment options should be considered. For more interaction (complete) data (6 items in total) on ezetimibe, please visit the HSDB record page. An 8-week toxicity study in C57BL/6 mice (10 mg/kg/day orally) showed that ezetimibe (SCH 58235) did not cause significant changes in body weight (change <5%), liver function (ALT, AST), or kidney function (creatinine, BUN) [1].
A 12-week study in ZDF rats (5 mg/kg/day orally) showed no significant histopathological abnormalities in the liver, kidneys, spleen, or intestines. Serum electrolytes and hematological parameters were all within the normal range [2].
Ezetimibe (SCH 58235) has a plasma protein binding rate of 90-95% in humans [1].

[1]. Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis. Free Radic Biol Med. 2016 Sep 12;99:520-532.

[2]. Ezetimibe improves hepatic steatosis in relation to autophagy in obese and diabetic rats. World J Gastroenterol. 2015 Jul 7;21(25):7754-63.

Therapeutic Uses
Ezetimibe can be used alone or in combination with other lipid-lowering drugs (such as HMG-CoA reductase inhibitors (statins), fenofibrate) as an adjunct to dietary therapy for the treatment of primary hypercholesterolemia and mixed dyslipidemia, homozygous familial hypercholesterolemia, and/or homozygous familial phytosterolemia. /US Product Label Includes/ Ezetimibe can be used alone or in combination with statins as an adjunct to dietary therapy to reduce elevated serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apo B) levels in primary (heterozygous familial and non-familial) hypercholesterolemia. Ezetimibe and simvastatin fixed-dose combination preparations can be used as adjunctive therapy to treat primary hypercholesterolemia or mixed dyslipidemia, reducing elevated serum total cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, and non-HDL cholesterol levels, and increasing HDL cholesterol levels. Ezetimibe can also be used in combination with fenofibrate as adjunctive therapy to treat mixed dyslipidemia, reducing elevated serum total cholesterol, LDL cholesterol, apolipoprotein B, and non-HDL cholesterol levels. /US Product Label/
Ezetimibe can be used as adjunctive therapy to reduce elevated serum sitosterol and campesterol levels in patients with homozygous familial sitosterolemia. /US Product Label Includes/
Ezetimibe can be used in combination with atorvastatin or simvastatin to lower elevated serum total cholesterol and low-density lipoprotein cholesterol levels in patients with homozygous familial hypercholesterolemia, as adjunctive therapy to other lipid-lowering therapies (such as plasma low-density lipoprotein ablation), or when other lipid-lowering therapies are unavailable. /US Product Label Includes/
This is a retrospective study that included all pediatric patients who received ezetimibe monotherapy for hypercholesterolemia and had follow-up clinical and lipid outcomes. Of the 36 identified patients, 26 had lipoprotein profiles suggestive of familial hypercholesterolemia (FH), and 10 had lipoprotein profiles suggestive of familial mixed hyperlipidemia (FCHL). After a mean of 105 days (range 32–175 days) of ezetimibe treatment, total cholesterol (TC) levels in patients with fibrocystic liver disease (FH) decreased from 7.3 ± 1.0 mmol/L to 5.7 ± 1.0 mmol/L (P < 0.0001), and low-density lipoprotein cholesterol (LDL-C) levels decreased from 5.3 ± 0.9 mmol/L to 3.9 ± 0.8 mmol/L (P < 0.0001). In patients with functional fibrocystic liver disease (FCHL), TC levels decreased from 6.4 ± 2.0 mmol/L to 5.6 ± 0.4 mmol/L (P ≤ 0.002), and LDL-C levels decreased from 4.7 ± 1.0 mmol/L to 3.8 ± 0.6 mmol/L (P ≤ 0.005). The mean LDL-C value decreased by 1.5 ± 0.9 mmol/L across all patients, representing a reduction of 28%. Following ezetimibe treatment, there were no significant changes in triglyceride and high-density lipoprotein cholesterol (HDL-C) levels. Patients received ezetimibe treatment for up to 3.5 years without any drug-related adverse events. At a median duration of 13.6 months (range 1–44 months) after initiation of ezetimibe treatment, LDL-C levels remained at 4.0 ± 0.6 mmol/L. In this small retrospective study of children and adolescents with hypercholesterolemia, ezetimibe demonstrated safety and efficacy in lowering LDL-C levels. Drug Warnings: Ezetimibe is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminase (transaminase) levels when used in combination with HMG-CoA reductase inhibitors (statins). The Zetia controlled clinical trial database (placebo-controlled) included 2396 patients with a median treatment duration of 12 weeks (range 0–39 weeks). In the Zetia group, 3.3% and 2.9% of patients in the placebo group discontinued treatment due to adverse reactions. The most common adverse reactions leading to Zetia treatment discontinuation, with a higher incidence than in the placebo group, were: arthralgia (0.3%); dizziness (0.2%); and elevated gamma-glutamyl transferase (0.2%). In the database of controlled clinical trials of Zetia monotherapy involving 2396 patients, the most frequently reported adverse reactions (incidence ≥2% and higher than in the placebo group) were: upper respiratory tract infection (4.3%), diarrhea (4.1%), arthralgia (3.0%), sinusitis (2.8%), and extremity pain (2.7%). In the database of controlled clinical trials of Zetia + statins involving 11308 patients, with a median treatment duration of 8 weeks (range 0 to 112 weeks), 4.0% of patients in the Zetia + statin group and 3.3% of patients in the statin monotherapy group discontinued treatment due to adverse reactions. In patients receiving Zetia in combination with statins, the most common adverse reactions leading to treatment discontinuation and occurring at a higher rate than with statin monotherapy included: elevated alanine aminotransferase (0.6%), myalgia (0.5%), fatigue, elevated aspartate aminotransferase (AST), headache, and limb pain (all 0.2%). In a database of controlled clinical trials of Zetia in combination with statins involving 11,308 patients, the most frequently reported adverse reactions (incidence ≥2% and higher than with statin monotherapy) included: nasopharyngitis (3.7%), myalgia (3.2%), upper respiratory tract infection (2.9%), arthralgia (2.6%), and diarrhea (2.5%). Post-marketing surveillance experience with Zetia has included case reports of myopathy and rhabdomyolysis. Most patients experiencing rhabdomyolysis had previously taken statins before starting Zetia. However, reports indicate that rhabdomyolysis can occur with eteravir monotherapy and when used in combination with medications known to increase the risk of rhabdomyolysis (such as fibrates). If myopathy is diagnosed or suspected, eteravir and any statins or fibrates the patient is taking concurrently should be discontinued immediately. The presence of muscle symptoms and creatine phosphokinase (CPK) levels exceeding the upper limit of normal (ULN) by more than 10 times are indicative of myopathy. For more complete data on drug warnings for ezetimibe (15 in total), please visit the HSDB record page.
Pharmacodynamics
Ezetimibe has been shown to lower total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), and triglyceride (TG) levels, and to raise high-density lipoprotein cholesterol (HDL-C) levels in patients with hyperlipidemia. Compared with ezetimibe alone or with statins or fenofibrate, ezetimibe is more effective when used in combination with these two drugs. In clinical trials in patients with homozygous and heterozygous familial hypercholesterolemia and phytosterolemia, the recommended therapeutic dose of ezetimibe effectively reduced low-density lipoprotein cholesterol (LDL-C) levels by 15-20% while increasing high-density lipoprotein cholesterol (HDL-C) levels by 2.5-5%. The effect of increased ezetimibe exposure in patients with moderate to severe hepatic impairment has not been evaluated—patients meeting these criteria should avoid using ezetimibe. Post-marketing reports indicate that patients taking ezetimibe may develop myopathy and rhabdomyolysis, and this risk appears to be exacerbated in patients who have received or recently received statin therapy.

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Ezetimibe (SCH 58235) is a selective NPC1L1 inhibitor that blocks intestinal cholesterol absorption and hepatic cholesterol reabsorption[1].
Its protective effects against non-alcoholic steatohepatitis (NASH) and hepatic steatosis involve two key mechanisms: inhibition of NPC1L1 to reduce lipid accumulation, and activation of Nrf2 to enhance antioxidant defense and reduce oxidative stress[1].
It modulates hepatic autophagy by upregulating autophagy flux, promotes lipid droplet degradation, and reduces intracellular lipid accumulation in obesity/diabetes models[2].
Clinically, ezetimibe is indicated for the treatment of hypercholesterolemia, either alone or in combination with statins, to lower serum cholesterol levels. Low-density lipoprotein cholesterol (LDL-C) levels[1]
Preclinical studies support its potential as a treatment for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)[1][2]

C24H21F2NO3

409.4

409.148

C, 70.41; H, 5.17; F, 9.28; N, 3.42; O, 11.72

163222-33-1

Ezetimibe;163222-33-1

150311

White to off-white solid powder

1.3±0.1 g/cm3

654.9±55.0 °C at 760 mmHg

164-166℃

349.9±31.5 °C

0.0±2.1 mmHg at 25°C

1.624

3.26

2

5

6

30

567

3

FC1C([H])=C([H])C(=C([H])C=1[H])N1C([C@]([H])(C([H])([H])C([H])([H])[C@@]([H])(C2C([H])=C([H])C(=C([H])C=2[H])F)O[H])[C@@]1([H])C1C([H])=C([H])C(=C([H])C=1[H])O[H])=O

OLNTVTPDXPETLC-XPWALMASSA-N

InChI=1S/C24H21F2NO3/c25-17-5-1-15(2-6-17)22(29)14-13-21-23(16-3-11-20(28)12-4-16)27(24(21)30)19-9-7-18(26)8-10-19/h1-12,21-23,28-29H,13-14H2/t21-,22+,23-/m1/s1

(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one

SCH-58235; SCH 58235; SCH-58235; SCH58235; trade names: Zetia, Ezetrol

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)