Ezetimibe

Molecular formula C24H21F2NO3 Molecular welgM 409.42 CAS Registry No 163222-33-1 Merck Index 13,3949 

Sample preparation Extract bile with 1.5 vol of MeCN. 

Mobile phase Gradient. MeCNilOO mM pH 6 ammonium acetate from 30 70 to 100 0 over 40 min (concave gradient (Waters Expert-Ease Curve 10)). 

Van Heek, M. Farley, C. Compton, D.S. Hoos, L. Alton, K.B. Sybertz, E.J. Davis, H.R. Jr. Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235, and its glucuronide, SCH60663. Br.J.Pharmacol., 2000,129, 1748-1754. 

Sample preparation For unconjugated ezetimibe, add 100 iL 513 ng/mL IS in water and 1 mL water to 200 p.L plasma, add 8 mL 1-chlorobutane. For total ezetimibe, add 100 xL 513 ng/mL IS in water, 500 p,L 500 mM pH 5.0 sodium acetate buffer, and 50 xL /3-gIucuronidase (100 000 U/mL) to 200 p.L plasma, heat at 50° for 1 h, add 500 p,L 1 M sodium borate solution, add 8 mL 1-chlorobutane. Shake each mixture for 15 min and centrifuge at 491 g for 10 min. Evaporate the organic layer to dryness under reduced pressure, reconstitute the residue with 500 p-L MeOH, evaporate to dr3mess, reconstitute with 50 pL MeOH, inject an aliquot. 

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Caco-2 cells and ezetimibe, a potent inhibitor of chloresterol absorption in humans, it was reported that (1) carotenoid transport was inhibited by ezetimibe up to 50% and the extent of that inhibition diminished with increasing polarity of the carotenoid molecule, (2) the inhibitory effects of ezetimibe and the antibody against SR-BI on P-carotene transport were additive, and (3) ezetimibe may interact physically with cholesterol transporters as previously suggested - and also down-regulate the gene expression of three surface receptors, SR-BI, NPCILI, and ABCAl. 

During, A., Dawson, H.D., and Harrison, E.H., Carotenoid transport is decreased and expression of the lipid transporters SR-Bl, NPCILI, and ABCAl is down-regulated in Caco-2 cells treated with ezetimibe, J. Nutr., 135, 2305, 2005. 

Metoprolol 1 00 mg by mouth twice daily Hydrochlorothiazide 25 mg by mouth daily Vytorin 10/40 (ezetimibe 10 mg/simvastatin 40 mg) by mouth daily... 

Combination drug therapy is an effective means to achieve greater reductions in LDL cholesterol (statin + ezetimibe or bile acid resin, bile acid resin + ezetimibe, or three-drug combinations) as well as raising HDL cholesterol and lowering serum triglycerides (statin + niacin or fibrate). 

Ezetimibe 1 0 mg tablet 10 mg once daily The overall incidence of adverse events reported with ezetimibe alone was similar to that reported with placebo and generally similar between ezetimibe with a statin and statin alone. The frequency of increased transaminases was slightly higher in patients receiving ezetimibe plus a statin compared with those receiving statin monotherapy (1.3% versus 0.4%). 

Ezetimibe and 10 mg/10 mg, The dosage range is See entries on prior page for each drug (ezetimibe and... 

Ezetimibe is the first drug in a new class of agents referred to as cholesterol absorption inhibitors. Ezetimibe blocks biliary and dietary cholesterol as well as phytosterol (plant sterol)... 

Ezetimibe reduces LDL cholesterol by an average of 18% (Table 9-8). However, larger reductions can be seen in some individuals, presumably due to higher absorption of cholesterol. These individuals appear to have a blunted response to statin therapy. Ezetimibe lowers triglycerides by 7% to 9% and modestly increases HDL cholesterol. 

Once absorbed, ezetimibe undergoes extensive glucuronida-tion in the intestinal wall to the active metabolite (ezetimibe glucuronide). Ezetimibe and the active metabolite are entero-hepatically recirculated back to the site of action, which limits systemic exposure and may explain the low incidence of adverse effects (Table 9-9). Ezetimibe alone or with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in LFTs. Currently, clinical trials designed to determine ezetimibe s effects on CHD morbidity and mortality have not been completed. The time until maximum effect on lipids for ezetemibe is generally 2 weeks. 

A statin combined with a resin results in similar reductions in LDL cholesterol as those seen with ezetimibe. However, the magnitude of triglyceride reduction is less with a resin compared to ezetimibe, and this should be considered in patients with higher baseline triglyceride levels. In addition, gastrointestinal adverse events and potential drug interactions limit the utility of this combination. 

Ezetimibe and a resin can also be combined. A study which assessed the effects of adding ezetimibe to ongoing resin therapy showed an additional 19% reduction in LDL cholesterol and an additional 14% reduction in triglycerides. This combination was well tolerated.41... 

The first study was conducted to determine whether carotenoids and cholesterol share common pathways (transporters) for their intestinal absorption (During et al., 2005). Differentiated Caco-2 cells on membranes were incubated (16 h) with a carotenoid (1 pmol/L) with or without ezetimibe (EZ Zetia, an inhibitor of cholesterol transport), and with or without antibodies against the receptors, cluster determinant 36 (CD36) and scavenger receptor class B, type I (SR-BI). Carotenoid transport in Caco-2 cells (cellular uptake + secretion) was decreased by EZ (lOmg/L) as follows P-C and a-C (50% inhibition) P-cryptoxanthin and LYC (20%) LUT ZEA (1 1) (7%). EZ reduced cholesterol transport by 31%, but not retinol transport. P-Carotene transport was also inhibited by anti-SR-BI, but not by anti-CD36. The inhibitory effects of EZ and anti-SR-BI on P-C transport... 

As demonstrated above, the uptake of [1-C at the apical membrane of differentiated Caco-2 cells occurs via a saturable, facilitated mechanism and is inhibited by Ezetimibe, a clinically used inhibitor of cholesterol absorption. Carotenoids secreted at the basolateral membrane were associated... 

Currently, there are a number of systemic and intestine-selective MTP inhibitors, including lomitapide (23, BMS-201038, AEGR-733), implitapide (24), JTT-130, SLx-4090, and R-256918 (latter three structures not disclosed) believed to be in active development [60]. In a meta-analysis of three Phase II clinical trials, lomitapide as monotherapy or in combination with ezetimibe, atorvastatin, or fenofibrate significantly reduced LDL cholesterol (up to 35% as monotherapy and 66% in combination with atorvastatin) and was well tolerated with less than 2% discontinuation due to abnormal liver function [61]. Lomitapide has also been granted orphan drug status for the treatment of homozygous familial hypercholesterolemia [59]. Results of a Phase II study of JTT-130 for type 2 diabetes are expected in August 2010 [59,60]. 

Ezetimibe Blocks cholesterol absorption across the intestinal border i Cholesterol T LDL... 

SimvastatirYezetimibe Simvastatin/ezetimibe 10 mg/ Simvastatin/ezetimibe Simvastatin/... 

Combination therapy with a statin and ezetimibe is also rational because ezetimibe inhibits cholesterol absorption across the gut border and adds 12% to 20% further reduction when combined with a statin or other drugs. 

Ezetimibe interferes with the absorption of cholesterol from the brush border of the intestine, a novel mechanism that makes it a good choice for adjunctive therapy. It is approved as both monotherapy and for use with a statin. The dose is 10 mg once daily, given with or without food. When used alone, it results in an approximate 18% reduction in LDL cholesterol. When added to a statin, ezetimibe lowers LDL by about an additional 12% to 20%. A combination product (Vytorin) containing ezetimibe 10 mg and simvastatin 10, 20, 40, or 80 mg is available. Ezetimibe is well tolerated approximately 4% of patients experience GI upset. Because cardiovascular outcomes with ezetimibe have not been evaluated, it should be reserved for patients unable to tolerate statin therapy or those who do not achieve satisfactory lipid lowering with a statin alone. 

Primary hypercholesterolemia (familial hypercholesterolemia, familial combined hyperlipidemia, type Ila hyperlipoproteinemia) is treated with BARs, statins, niacin, or ezetimibe. 

Eye exposure, to hydrogen fluoride, 14 18 Eye irritation, in spas/hot tubs, 26 197-198 Eyehners, 7 862 Eye makeup, 7 861-862 Eye shadows, 7 862 Eyewash fountains, 21 849 Eyewear, polycarbonate, 19 809 Eyring equation, 13 407 Eyring transfer matrix technique, 1 32 Ezetimibe (zetia), 5 143—144... 

Ezetrol contains ezetimibe, which selectively inhibits absorption of cholesterol in the intestine. It is used as monotherapy or in combination with other drug therapy as an adjunct to lifestyle measures in patients with hypercholesterolaemia. 

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