NPC1L1; Nrf2

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]

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]

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.

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].

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.

Absorption, Distribution and Excretion
Administration of a single 10-mg dose of ezetimibe in fasted adults resulted in peak plasma concentrations (Cmax) of 3.4-5.5 ng/mL within 4-12 hours (Tmax). The Cmax of the major pharmacologically-active metabolite, ezetimibe-glucuronide, was 45-71 ng/mL and its Tmax was 1-2 hours. Food consumption has minimal effect on ezetimibe absorption, but the Cmax is increased by 38% when administered alongside a high-fat meal. The true bioavailability of ezetimibe cannot be determined, as it is insoluble in aqueous media suitable for intravenous injection.
Approximately 78% and 11% of orally administered radiolabelled ezetimibe are recovered in the feces and urine, respectively. Unchanged parent drug is the major component in feces and accounts for approximately 69% of an administered dose, while ezetimibe-glucuronide is the major component in urine and accounts for approximately 9% of an administered dose. High recovery of unchanged parent drug in feces suggests low absorption and/or hydrolysis of ezetimibe-glucuronide secreted in the bile.
The relative volume of distribution of ezetimibe is 107.5L.
There are no pharmacokinetic data available on the clearance of ezetimibe.
Ezetimibe is the first member of a new class of selective cholesterol absorption inhibitors. The drug and its active glucuronide metabolite impair the intestinal reabsorption of both dietary and hepatically excreted biliary cholesterol through inhibition of a membrane transporter yet to be identified. Absorption of ezetimibe is rapid and not altered by food content following oral administration. The drug is not metabolized by the cytochrome P450 system but extensive glucuronidation takes place in the intestine. Consequently, plasma concentrations of ezetimibe represent approximately 10% of total ezetimibe in plasma. Enterohepatic recirculation observed for ezetimibe and its glucuronimide significantly increases the residence time of these compounds in the intestine, at their site of action. Elimination of ezetimibe glucuronimide appears impaired in elderly patients and patients with renal insufficiency with plasma concentrations increased 1.5- to 2-fold. So far, no drug interaction study has been associated with major changes in either the pharmokinetics of ezetimibe or coadministered drugs.
Ezetimibe lowers plasma cholesterol levels by inhibiting the uptake of cholesterol in the intestine. Due to extensive enterohepatic circulation of ezetimibe, relative low doses are required to be effective. In blood and bile the majority of ezetimibe is present as a glucuronide-conjugate, which is formed in the enterocyte. Presently, it is not clear which mechanisms are responsible for this efficient enterohepatic circulation. Abcc2, Abcc3 and Abcg2 are ABC transporters, which are expressed in both liver and intestine and are capable of transporting glucuronidated compounds. The aim of this study was to investigate the contribution of these transporters in the enterohepatic cycling of ezetimibe-glucuronide (Ez-gluc). Transport studies were performed in plasma membrane vesicles from ABCC2, ABCC3 and ABCG2 expressing Sf21 insect cells. Furthermore, intestinal explants from wild-type and Abcc3-/- mice were used to study vectorial transport in an Ussing chamber setup. Finally, biliary excretion of Ez-gluc was measured in vivo after duodenal delivery of ezetimibe in wild-type, Abcc3-/-, Abcc2-/-, Abcg2-/- and Abcg2-/-/Abcc2-/- mice. ABCC3-, ABCC2- and ABCG2-mediated transport was dose dependently inhibited by Ez-gluc. In the Ussing chamber Ez-gluc recovered from the basolateral side was significantly reduced in duodenal (2.2%), in jejunal (23%) and in ileal (23%) tissue of Abcc3-/- compared to wild-type mice. Biliary excretion of Ez-gluc was significantly reduced in Abcc3-/- (34%), Abcc2-/- (56%) and Abcg2-/-/Abcc2-/- (2.5%) compared to wild-type mice. These data demonstrate that enterohepatic circulation of Ez-gluc strongly depends on the joint function of Abcc3, Abcc2 and Abcg2.
It is not known whether ezetimibe is excreted into human breast milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma.
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of Zetia to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection.

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Metabolism / Metabolites
In humans, ezetimibe is rapidly and extensively metabolized via a phase II glucuronide conjugation reaction in the small intestine and liver to form its main phenolic metabolite, ezetimibe glucuronide. The main human liver and/or intestinal uridine 5′-diphosphate (UDP)-glucuronosyltransferase (UGT) enzymes responsible for the glucuronidation of ezetimibe were shown to be UGT1A1, 1A3, and 2B15 _in vitro_. Minimal phase I reaction involving oxidation of ezetimibe also occurs to form SCH 57871, and human jejunum microsomes also produced trace levels of a benzylic glucuronide (SCH 488128). Ezetimibe glucuronide accounts for 80-90% of the total circulating compound in plasma, and retains some pharmacological activity in inhibiting intestinal cholesterol uptake. In humans, ezetimibe and ezetimibe-glucuronide constitutes approximately 93% of the total drug in plasma. Plasma concentration-time profiles exhibit multiple peaks, suggestive of enterohepatic recycling, and about 20% of the drug distributed is reabsorbed due to enterohepatic recirculation.
Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated. In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting 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 for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling. Following oral administration of (14)C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma. Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.
Ezetimibe has known human metabolites that include Ezetimibe-glucuronide.

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Biological Half-Life
Both ezetimibe and ezetimibe-glucuronide display an approximate half-life of 22 hours.
Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide.

Hepatotoxicity
Therapy with ezetimibe alone or in combination with other lipid lowering agents is associated with a low rate of serum enzyme elevations (0.5% to 1.5%), but most elevations are self-limited and not associated with jaundice or symptoms. In large randomized controlled trials, ezetimibe by itself has not been associated with a higher rate of serum ALT elevation than occurs with placebo therapy. However, the addition of ezetimibe to statin therapy has been associated with a slight increase in the likelihood of serum aminotransferase elevations or rates of discontinuation due to liver test abnormalities. Clinically apparent acute liver injury due to ezetimibe has been reported, but is rare. Furthermore, because this agent is often used in combination with other cholesterol lowering drugs, the role of ezetimibe in these reports is not always well defined. The latency to onset of clinically apparent liver injury attributed to ezetimibe has ranged from 2 to 10 months and the pattern of serum enzyme elevations has ranged from hepatocellular to cholestatic. Cases of autoimmune hepatitis-like injury have been described in patients taking the combination of ezetimibe and a statin, and the role of ezetimibe in these reactions is difficult to assign (Case 1). A single instance of vanishing bile duct syndrome due to ezetimibe has been described in a patient who continued on ezetimibe for several months despite presence of jaundice.
Likelihood score: C (probable rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Data from 2 mothers indicate that levels of ezetimibe and its active metabolite appear in very low amounts in milk and serum levels in infants predicted by a pharmacokinetic model are considerably lower than in adults. Ezetimibe appears to be acceptable during breastfeeding. Ezetimibe in combination with a statin (e.g., atorvastatin, simvastatin) should be avoided in nursing mothers.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Ezetimibe and ezetimibe-glucuronide are >90% bound to human plasma proteins. The mean _in vitro_ protein binding ranged from 99.5% to 99.8% for ezetimibe and 87.8% to 92.0% for ezetimibe-glucuronide.

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Interactions
Pharmacokinetic or pharmacodynamic interaction /with warfarin/ is unlikely, based on one small study. Increased international normalized ratio (INR) with concomitant use of ezetimibe and warfarin has been reported during postmarketing experience; however, most patients also were receiving other drugs. Monitor INR if ezetimibe is initiated in a patient receiving warfarin.
Potential pharmacokinetic interaction (increased peak plasma ezetimibe concentration and AUC, increased cyclosporine AUC). The degree of exposure to ezetimibe may be greater in patients with severe renal insufficiency. Risk of myopathy/rhabdomyolysis is increased following concomitant administration of the fixed combination of ezetimibe and simvastatin (particularly at higher dosages) with cyclosporine. Because of increased exposure to ezetimibe and cyclosporine, use concomitantly with caution and monitor cyclosporine concentrations. If used concomitantly, dosage of the fixed-combination preparation should not exceed 10 mg of ezetimibe and 10 mg of simvastatin daily.
Potential pharmacokinetic (decreased AUC of ezetimibe) and pharmacodynamic (reduced LDL-cholesterol lowering effect) interaction. Ezetimibe should be administered at least 2 hours before or at least 4 hours after administration of the bile acid sequestrant.
Pharmacokinetic interaction (increased plasma ezetimibe concentrations) observed when used concomitantly with fenofibrate or gemfibrozil. Fibric acid derivatives may increase cholesterol excretion into bile, leading to cholelithiasis, and ezetimibe has been shown to increase cholesterol in the gall bladder bile in animals. In clinical studies, cholecystectomy has been reported in 1.7% of patients receiving ezetimibe concomitantly with fenofibrate and in 0.6% of those receiving fenofibrate monotherapy. Concomitant use with a fibric acid derivative other than fenofibrate currently is not recommended pending further accumulation of data in humans. If cholelithiasis is suspected in a patient receiving ezetimibe with fenofibrate, gallbladder studies should be performed, and alternative antilipemic therapy should be considered.
For more Interactions (Complete) data for Ezetimibe (6 total), please visit the HSDB record page.

[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 is used alone or in combination with other antilipemic agents (i.e., a hydroxymethylglutaryl-coenzyme A [HMG-CoA] reductase inhibitor (statin), fenofibrate) as an adjunct to dietary therapy in the treatment of primary hypercholesterolemia and mixed dyslipidemia, homozygous familial hypercholesterolemia, and/or homozygous familial sitosterolemia. /Included in US product label/
Ezetimibe is used alone or in combination with a statin as an adjunct to dietary therapy to decrease elevated serum total cholesterol, low-density lipoprotein (LDL)-cholesterol, and apolipoprotein B (apo B) concentrations in the treatment of primary (heterozygous familial and nonfamilial) hypercholesterolemia. Ezetimibe in fixed combination with simvastatin is used as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, triglyceride, and non-HDL-cholesterol concentrations, and to increase HDL-cholesterol concentrations in the treatment of primary hypercholesterolemia or mixed dyslipidemia. Ezetimibe also is used in combination with fenofibrate as an adjunct to dietary therapy to decrease elevated serum total cholesterol, LDL-cholesterol, apo B, and non-HDL-cholesterol concentrations in the treatment of mixed dyslipidemia. /Included in US product label/
Ezetimibe is used as an adjunct to dietary therapy to decrease elevated serum sitosterol and campesterol concentrations in patients with homozygous familial sitosterolemia. /Included in US product label/
Ezetimibe may be used in combination with atorvastatin or simvastatin to decrease elevated serum total and LDL-cholesterol concentrations in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g., plasma LDL apheresis) or when such therapies are not available. /Included in US product label/
This is a retrospective review of all pediatric patients who received ezetimibe monotherapy as treatment for hypercholesterolemia and for whom follow-up clinical and lipid results were available. Of 36 identified patients, 26 had lipoprotein profiles suggestive of familial hypercholesterolemia (FH), and 10 had profiles suggestive of familial combined hyperlipidemia (FCHL). After a mean 105 days of treatment with ezetimibe (range, 32-175 days), total cholesterol (TC) levels decreased from 7.3 +/- 1.0 mmol/L to 5.7 +/- 1.0 mmol/L (P < .0001), and low-density lipoprotein cholesterol (LDL-C) levels decreased from 5.3 +/- 0.9 mmol/L to 3.9 +/- 0.8 (P < .0001) in patients with FH. In patients with FCHL, TC levels decreased from 6.4 +/- 2.0 mmol/L to 5.6 +/- 0.4 mmol/L (P < or = .002), and LDL-C levels decreased from 4.7 +/- 1.0 mmol/L to 3.8 +/- 0.6 mmol/L (P < or = .005). For all patients, the mean decrease in individual LDL-C values was 1.5 +/- 0.9 mmol/L or 28%. There was no significant change in triglyceride or high-density lipoprotein cholesterol levels with ezetimibe. Patients were maintained on ezetimibe with no adverse effects attributable to the medication for as long as 3.5 years. At a mean of 13.6 months (range, 1-44 months) after the initiation of ezetimibe, LDL-C levels remained decreased at 4.0 +/- 0.6 mmol/L. In this small retrospective series of children and adolescents with hypercholesterolemia, ezetimibe was safe and effective in lowering LDL-C levels.

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Drug Warnings
Ezetimibe, in combination with a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), is contraindicated in patients with active liver disease or unexplained, persistent increases in serum aminotransferase (transaminase) concentrations.
In the Zetia controlled clinical trials database (placebo-controlled) of 2396 patients with a median treatment duration of 12 weeks (range 0 to 39 weeks), 3.3% of patients on Zetia and 2.9% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Zetia that led to treatment discontinuation and occurred at a rate greater than placebo were: Arthralgia (0.3%); dizziness (0.2%); and gamma-glutamyltransferase increased (0.2%) The most commonly reported adverse reactions (incidence =2% and greater than placebo) in the Zetia monotherapy controlled clinical trial database of 2396 patients were: upper respiratory tract infection (4.3%), diarrhea (4.1%), arthralgia (3.0%), sinusitis (2.8%), and pain in extremity (2.7%).
In the Zetia + statin controlled clinical trials database of 11,308 patients with a median treatment duration of 8 weeks (range 0 to 112 weeks), 4.0% of patients on Zetia + statin and 3.3% of patients on statin alone discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Zetia + statin that led to treatment discontinuation and occurred at a rate greater than statin alone were: Alanine aminotransferase increased (0.6%) Myalgia (0.5%) Fatigue, aspartate aminotransferase increased, headache, and pain in extremity (each at 0.2%) The most commonly reported adverse reactions (incidence =2% and greater than statin alone) in the Zetia + statin controlled clinical trial database of 11,308 patients were: nasopharyngitis (3.7%), myalgia (3.2%), upper respiratory tract infection (2.9%), arthralgia (2.6%) and diarrhea (2.5%).
In post-marketing experience with Zetia, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin prior to initiating Zetia. However, rhabdomyolysis has been reported with Zetia monotherapy and with the addition of Zetia to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates. Zetia and any statin or fibrate that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. The presence of muscle symptoms and a CPK level >10 times the upper limit of normal (ULN) indicates myopathy.
For more Drug Warnings (Complete) data for Ezetimibe (15 total), please visit the HSDB record page.

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Pharmacodynamics
Ezetimibe was shown to reduce the levels of total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), and triglycerides (TG), and increase high-density lipoprotein cholesterol (HDL-C) in patients with hyperlipidemia. This therapeutic effect was more profound when ezetimibe was co-administered with a statin or fenofibrate compared to either treatment alone. In clinical trials involving patients with homozygous and heterozygous familial hypercholesterolemia and in those with sitosterolemia, a recommended therapeutic dose of ezetimibe was effective in reducing the LDL levels by 15-20% while increasing HDL-C by 2.5-5%. The effects of increased exposure to ezetimibe secondary to moderate-severe hepatic impairment have not been assessed - patients meeting these criteria should avoid the use of ezetimibe. Post-marketing reports indicate the potential for myopathy and rhabdomyolysis in patients taking ezetimibe, and this risk appears to be exacerbated in patients concurrently receiving, or having recently received, statin therapy.

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)