Singapore Drugs Database

Indication

Ezetimibe is indicated to reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary hyperlipidemia, alone or in combination with an HMG-CoA reductase inhibitor (statin), reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia in combination with fenofibrate, reduce elevated total-C and LDL-C in patients with homozygous familial hypercholesterolemia (HoFH), in combination with atorvastatin or simvastatin, and to reduce elevated sitosterol and campesterol in patients with homozygous sitosterolemia (phytosterolemia) [FDA Label].

Mechanism of Action

Ezetimibe mediates its blood cholesterol-lowering effect via selectively inhibiting the absorption of cholesterol and phytosterol by the small intestine without altering the absorption of fat-soluble vitamins and nutrients [A15202]. The primary target of ezetimibe is the cholesterol transport protein Niemann-Pick C1-Like 1 (NPC1L1) protein. NPC1L1 is expressed at the enterocyte/ gut lumen (apical) as well as the hepatobiliary (canalicular) interface and plays a role in facilitating internalization of free cholesterol into the enterocyte in conjunction with the adaptor protein 2 (AP2) complex and clathrin [A33309]. Once cholesterol in the gut lumen or bile is incorporated into the cell membrane of enterocytes, it can bind to the sterol-sensing domain of NPC1L1 and form a NPC1L1/cholesterol complex. The complex can then be internalized or endocytosed by joining to AP2 clathrin, forming a vesicle complex that is translocated for storage in the endocytic recycling compartment [A33309]. Ezetimibe does not require exocrine pancreatic function for its pharmacological activity; rather, it localizes and appears to act at the brush border of the small intestine. Ezetimibe selectively blocks the NPC1L1 protein in the jejunal brush border, reducing the uptake of intestinal lumen micelles into the enterocyte [A33309]. Overall, ezetimibe causes a decrease in the delivery of intestinal cholesterol to the liver and reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. While the full mechanism of action of ezetimibe in reducing the entry of cholesterol into both enterocytes and hepatocytes is not fully understood, a study proposed that ezetimibe prevents the NPC1L1/sterol complex from interacting with AP2 in clathrin coated vesicles and induces a conformational change in NPC1L1, rendering it incapable of binding to sterols [A33309]. Another study suggested that ezetimibe disrupts the function of other proteins complexes involved in regulating cholesterol uptake, including the CAV1– annexin 2 heterocomplex [A33309].

Pharmacokinetics

Absorption

Administration of a single 10-mg dose of ezetimibe in fasted adults resulted in a peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were achieved within 4 to 12 hours (Tmax) [FDA Label]. The Cmax of the major pharmacologically-active metabolite, ezetimibe-glucuronide, was 45 to 71 ng/mL and the Tmax was between 1 and 2 hours [FDA Label]. Food consumption had minimal effect on ezetimibe absorption, but the Cmax was increased by 38% with consumption of high-fat meals [FDA Label]. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection [FDA Label].

Distribution

The relative volume of distribution of ezetimibe is 107.5L [F133].

Metabolism

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 glucuronidating ezetimibe were shown to be UGT1A1, 1A3 and 2B15 _in vitro_ [A15202]. 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) [A15202]. Ezetimibe glucuronide accounts for 80-90% of the total circulating compound in plasma, and retains some pharmacological activity in inhibiting intestinal cholesterol uptake [FDA Label]. In humans, ezetimibe and ezetimibe-glucuronide constitutes approximately 93% of the total drug in plasma [FDA Label]. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling [FDA Label], and about 20% of the drug distributed is reabsorbed due to enterohepatic re-circulation [F133].

Elimination

Clearance

There is no pharmacokinetic data available on the clearance of ezetimibe.

Toxicity

Oral LD50 and intraperitoneal LD50 in rat were >2000 mg/kg [MSDS]. Estimated oral LD50 values in mouse and dog are >5000 mg/kg and >3000 mg/kg, respectively [MSDS]. One case of accidental overdose occurred in clinical studies in one female patient with homozygous sitosterolemia receiving 120 mg/day for 28 days with no reported clinical or laboratory adverse events [FDA Label]. In case of overdose, symptomatic treatment is recommended [FDA Label].

Active Ingredient/Synonyms

Ezedoc | Ezetimiba | Ezetimibum | Ezetrol | Ezetimibe |