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

Abstract

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

Ezetimibe Ameliorates Metabolic Disorders and Microalbuminuria in Patients with Hypercholesterolemia

“…Serum LDL-chol levels are often insufficiently controlled by the suppression of cholesterol synthesis with a statin in patients with a genetic disorder or enhanced cholesterol absorption 10,11) . Ezetimibe is a novel agent that potently inhibits the intestinal absorption of cholesterol from dietary and biliary sources by blocking the Niemann-Pick C1-like 1 protein and is effective for therapy-resistant dyslipidemia [12][13][14] . Our data showed that ezetimibe therapy induced a 24.0% reduction in the serum LDL-chol level of our 38 patients; the decrease was 21.2% in patients subjected to ezetimibe monotherapy and 37.8% in those treated with an ezetimibe added to on-going statin therapy.…”

Requirement of Myosin Vb·Rab11a·Rab11-FIP2 Complex in Cholesterol-regulated Translocation of NPC1L1 to the Cell Surface

“…Genetic or pharmaceutical inactivation of NPC1L1 significantly inhibits cholesterol absorption and confers the resistance to diet-induced hypercholesterolemia (1,2,4). Ezetimibe, an NPC1L1-specific inhibitor, is currently used to prevent and treat cardiovascular diseases (5).…”

La Respuesta Terapéutica a Ezetimiba en Ratones C57BL/6 es Mediada por Cambios en la Expresión de NPC1L1, ABCG5 y ABCG8 en el Enterocito

“…Este resultado se explica porque la ezetimiba actúa inhibiendo selectivamente el transporte de colesterol a través de la pared intestinal sin afectar la hidrólisis intestinal de esteres de colesterol ni la absorción de los ácidos grasos aquí generados. El colesterol liberado producto de esta hidrólisis no es absorbido en presencia de ezetimiba (Davis & Veltri, 2007). En nuestro estudio, el tratamiento de los animales con ezetimiba no afectó significativamente los niveles séricos de triglicéridos (P = 0,162).…”