Therapeutic Indication
● Elevated Blood Lipids
● Elevated sitosterol and campesterol
● Obesity
Pharmacology
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. The primary target of ezetimibe is the cholesterol transport protein Niemann-Pick C1-Like 1 (NPC1L1) protein. NPC1L1 is expressed on enterocytes/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. Once cholesterol in the gut lumen or bile is incorporated into the cell membrane of enterocytes, it binds to the sterol-sensing domain of NPC1L1 and forms a NPC1L1/cholesterol complex. The complex is then internalized or endocytosed by joining to AP2 clathrin, forming a vesicle complex that is translocated for storage in the endocytic recycling compartment.
Absorption: 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)
Volume of distribution: The relative volume of distribution of ezetimibe is 107.5L
Protein binding: Ezetimibe and ezetimibe-glucuronide are >90% bound to human plasma proteins.
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.
Route of elimination: Approximately 78% and 11% of orally administered radiolabelled ezetimibe are recovered in the feces and urine, respectively. Both ezetimibe and ezetimibe-glucuronide display an approximate half-life of 22 hours.
Side Effects
Common side effects include:
● Unusual muscle weakness, tenderness, or pain;
● Nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
● Chest pain;
● Pancreatitis (severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate); or Fever, sore throat, and headache
Contraindication
Contraindications for the use of ezetimibe include hypersensitivity to any component of the formulation, concomitant use with an HMG-CoA reductase inhibitor in patients with active hepatic disease, or unexplained persistent elevations in serum transaminases. It is also contraindicated in pregnancy and breastfeeding when used in combination with an HMG-CoA reductase inhibitor Ezetimibe is not recommended in patients with moderate to severe hepatic impairment
Interaction
The following drugs may interact with ezetimibe:
Cyclosporine
Cholestyramine
Fenofibrate
Gemfibrozil