Disposition of the Selective Cholesterol Absorption Inhibitor Ezetimibe in Healthy Male Subjects

Patrick, James E.; Kosoglou, Teddy; Stauber, Kathe; Alton, Kevin B.; Maxwell, Stephen E.; Zhu, Yali; Statkevich, Paul; Iannucci, Robert; Chowdhury, Swapan K.; Affrime, Melton B.; Cayen, Mitchell N.

doi:10.1124/dmd.30.4.430

Cited by 154 publications

(116 citation statements)

References 17 publications

(12 reference statements)

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“…Ezetimibe is rapidly metabolized in the intestine to its phenolic glucuronide by uridine 5-diphosphate (UDP)-glucuronosyl-transferase 1A1, 1A3, and 2B15 7,8) .…”

Section: Metabolism Of Zetiamentioning

confidence: 99%

“…Autoradiographic analysis demonstrated that drug related material was located in the small intestinal villi, and concentrated at the enterocyte brush border 3,9) . In humans, ezetimibe is rapidly absorbed and primarily metabolized in the small intestine and liver to its glucuronide, with little oxidative cytochrome P450 mediated metabolism 7,8) . Ezetimibe and its glucuronide undergo enterohepatic recycling and have a plasma half-life of approximately 22 hours in humans.…”

Section: Metabolism Of Zetiamentioning

confidence: 99%

“…Since ezetimibe does not influence the activities of cytochrome P450 enzymes, no significant pharmacokinetic interactions occur with most medications. Pharmacokinetic interaction studies with ezetimibe in humans have found no significant changes in the plasma levels of many medications, including statins (atorvastatin, simvastatin, pravastatin, rosuvastatin, lovastatin, and fluvastatin), fibrates (gemfibrozil and fenofibrate), digoxin, glipizide, warfarin, and oral contraceptives (ethinyl estradiol and levonorgestrel) [6][7][8] .…”

Section: Metabolism Of Zetiamentioning

confidence: 99%

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Zetia: Inhibition of Niemann-Pick C1 Like 1 (NPC1L1) to Reduce Intestinal Cholesterol Absorption and Treat Hyperlipidemia

Davis¹,

Veltri²

2007

J Atheroscler Thromb

145

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Zetia (ezetimibe) is a selective cholesterol absorption inhibitor, which potently inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides or bile acids. Ezetimibe reduces the small intestinal enterocyte uptake and absorption of cholesterol by binding to Niemann-Pick C1 Like 1 (NPC1L1), which keeps cholesterol in the intestinal lumen for excretion. Ezetimibe undergoes glucuronidation to a single metabolite and localizes at the intestinal wall, where it binds with higher affinity for NPC1L1 than ezetimibe to prevent cholesterol absorption. Enterohepatic recirculation of ezetimibe and/or its glucuronide ensures repeated delivery to the intestinal site of action and limited peripheral exposure. Ezetimibe has no effect on the activity of major drug metabolizing enzymes (CYP450), which reduces any potential drug-drug interactions with other medications. Ezetimibe (10 mg/day) was found to inhibit cholesterol absorption by an average of 54% in hypercholesterolemic individuals and by 58% in vegetarians. Ezetimibe alone reduced plasma total and LDL-Cholesterol (18%) levels in patients with primary hypercholesterolemia. When ezetimibe was added to on-going statin treatment, an additional 25% reduction in LDL-C was found in patients with primary hypercholesterolemia and an additional 21% reduction in LDL-C in homozygous familial hypercholesterolemia. Ezetimibe in combination with statins produces additional reductions in plasma cholesterol levels and allows for more patients to achieve their LDL-C goals. . Zetia was identified through the characterization of the active biliary metabolites of its predecessor, SCH 48461, and extensive structure-activity relationship information obtained from a seven day cholesterol-fed hamster model 2) . Ezetimibe dose-dependently inhibited diet-induced hypercholesterolemia in hamsters with an ED50 of 0.04 mg/kg. In an acute model of intestinal absorption using radiolabeled cholesterol in rats, ezetimibe inhibited the appearance of radiolabeled cholesterol in plasma with an ED50 of 0.0015 mg/kg ninety minutes after dosing, indicating that the onset of activity was rapid 3) . Ezetimibe has proven to be most potent pre-clinically in cholesterol-fed rhesus monkeys with an ED50 0.0005 mg/kg/day. A single dose of the ezetimibe analog, SCH 48461, administered to cynomolgus monkeys fed a single cholesterol-containing meal caused a significant reduction of cholesterol in chylomicrons and chylomicron remnants during the postprandial phase without affecting triglyceride content 4) . Ezetimibe selectively inhibits the transport of cholesterol across the intestinal wall. Ezetimibe does not affect intestinal cholesteryl ester hydrolysis and the absorption of fatty acids thus generated. The free cholesterol from this hydrolysis, however, was not absorbed J Atheroscler

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“…Ezetimibe is rapidly metabolized in the intestine to its phenolic glucuronide by uridine 5-diphosphate (UDP)-glucuronosyl-transferase 1A1, 1A3, and 2B15 7,8) .…”

Section: Metabolism Of Zetiamentioning

confidence: 99%

Section: Metabolism Of Zetiamentioning

confidence: 99%

Section: Metabolism Of Zetiamentioning

confidence: 99%

See 1 more Smart Citation

Zetia: Inhibition of Niemann-Pick C1 Like 1 (NPC1L1) to Reduce Intestinal Cholesterol Absorption and Treat Hyperlipidemia

Davis¹,

Veltri²

2007

J Atheroscler Thromb

145

View full text Add to dashboard Cite

show abstract

“…[13][14][15] Ezetimibe is absorbed rapidly, extensively conjugated to glucuronide in the intestine, and circulated enterohepatically. 14,16,17 In clinical studies of patients with primary hypercholesterolemia, ezetimibe at 10 mg/d significantly decreased LDL-C by Ϸ20% after 12 weeks of therapy and had a safety profile similar to placebo. [17][18][19][20] Additionally, coadministration of ezetimibe with simvastatin or atorvastatin produced incremental LDL-C reductions and favorably affected total cholesterol, HDL cholesterol (HDL-C), and triglyceride levels.…”

mentioning

confidence: 99%

Efficacy and Safety of Ezetimibe Coadministered With Atorvastatin or Simvastatin in Patients With Homozygous Familial Hypercholesterolemia

2002

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Background-Patients with homozygous familial hypercholesterolemia (HoFH) have a high incidence of cardiovascular morbidity and mortality from premature atherosclerosis, and the efficacy of pharmacological therapy has been limited. We evaluated the efficacy, safety, and tolerability of ezetimibe, a novel cholesterol absorption inhibitor, in a multicenter, double-blind, randomized trial of HoFH patients receiving atorvastatin or simvastatin.

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“…The glucuronidated compound is thought to be more active than the parent at blocking cholesterol absorption. Both the parent compound and the glucuronidated compound are absorbed, and recirculated via hepatobiliary excretion [9]. Because no organ within the body seems to be a store of these compounds or have any direct biologic response to them, aside from the intestine, these agents are described as nonsystemic.…”

Section: Introductionmentioning

confidence: 99%

Ezetimibe: A novel cholesterol-lowering agent that highlights novel physiologic pathways

Patel

2004

Curr Cardiol Rep

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Ezetimibe is a US Food and Drug Administration-approved novel drug that targets the absorption of cholesterol in the intestine. The identification of this drug has also led to the elucidation of the dietary cholesterol receptor. Ezetimibe is efficacious as a plasma cholesterol-lowering agent as monotherapy, but its greatest utility seems to be as a combination with a low-dose statin, where it results in cholesterol lowering that is equivalent to using maximum-dose statins. It has a very favorable sideeffect profile, as well as a lack of drug-drug interactions. In addition, it prevents the absorption of noncholesterol sterols, such as plant sterols. In clinical studies, it has been shown to be highly efficacious in lowering plant sterols in a rare genetic disorder, sitosterolemia. Both the disease, as well as this therapeutic agent, have led to the concept that ezetimibe may be also useful in dissecting the role of these noncholesterol sterols in the pathogenesis of atherosclerosis.

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Disposition of the Selective Cholesterol Absorption Inhibitor Ezetimibe in Healthy Male Subjects

Cited by 154 publications

References 17 publications

Zetia: Inhibition of Niemann-Pick C1 Like 1 (NPC1L1) to Reduce Intestinal Cholesterol Absorption and Treat Hyperlipidemia

Zetia: Inhibition of Niemann-Pick C1 Like 1 (NPC1L1) to Reduce Intestinal Cholesterol Absorption and Treat Hyperlipidemia

Efficacy and Safety of Ezetimibe Coadministered With Atorvastatin or Simvastatin in Patients With Homozygous Familial Hypercholesterolemia

Ezetimibe: A novel cholesterol-lowering agent that highlights novel physiologic pathways

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