Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235, and its glucuronide, SCH60663

Abstract

1 Previous studies described the metabolism-based discovery of a potent, selective inhibitor of intestinal absorption of cholesterol, SCH58235 (Ezetimibe). Here we demonstrate that the phenolic glucuronide (SCH60663) of SCH58235, was more potent at inhibiting cholesterol absorption in rats than SCH58235, when administered by the intraduodenal route. 2 To understand the increased potency of the glucuronide, the metabolism and distribution of SCH58235 and SCH60663 were studied in bile duct-cannulated rats. 3 One minute after intraduodenal delivery of SCH58235, signi®cant levels of compound were detected in portal plasma; 495% was glucuronidated, indicating that the intestine was metabolizing SCH58235 to its glucuronide. When intraduodenally delivered as SCH58235, the compound was glucuronidated, moved through the intestinal wall, into portal plasma, through the liver, and into bile. However, when delivered as SCH60663, 495% of the compound remained in the intestinal lumen and wall, which may explain its increased potency. Signi®cant inhibition of cholesterol absorption and glucuronidation of SCH58235 occurred when SCH58235 was intravenously injected into bile duct-cannulated rats. Autoradiographic analysis demonstrated that drug related material was located throughout the intestinal villi, but concentrated in the villus tip. 4 These data indicate that (a) SCH58235 is rapidly metabolized in the intestine to its glucuronide; (b) once glucuronidated, the dose is excreted in the bile, thereby delivering drug related material back to the site of action and (c) the glucuronide is more potent than the parent possibly because it localizes to the intestine. Taken together, these data may explain the potency of SCH58235 in the rat (ID 50 =0.0015 mg kg 71) and rhesus monkey (ID 50 =0.0005 mg kg 71 ).

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

“…10 On the basis of the current results and similar LDL-C reductions in primary hypercholesterolemia, [17][18][19][20][21][22] it would be anticipated that ezetimibe would exert comparable actions in other forms of severe hypercholesterolemia. The effect of statins in HoFH seems to be significantly limited by the inability of these patients to effectively upregulate the LDL receptor, 10 whereas the primary mechanism responsible for ezetimibe-induced LDL-C lowering, inhibition of cholesterol absorption at the intestinal brush border, 13,14,23 seems to be largely unaffected by the pathophysiological milieu of HoFH.…”

“…10,12 Ezetimibe is the first of a new class of cholesterol absorption inhibitors that potently inhibits dietary and biliary cholesterol absorption at the brush border of the intestine without affecting the absorption of triglycerides or fat-soluble vitamins. [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.…”

“…[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.…”

Intestinal lipid absorption

“…Cholesterol in the body represents both endogenous sources (produced in the liver and peripheral tissues) and dietary sources absorbed from the intestine (186). The human diet provides ϳ400 mg of cholesterol daily, and the liver secretes ϳ1 g daily (66,194).…”

Ezetimibe-associated myopathy in monotherapy and in combination with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor

“…Some studies have investigated a new cholesterol absorption inhibitor (ezetimibe) in combination with statins (3)(4)(5)(6). Ezetimibe is the first member in a class of selective cholesterol absorption inhibitors that works by impairing the intestinal reabsorption of hepatically excreted biliary cholesterol and dietary cholesterol (7,8). Due to the potential risk of myopathy with statins alone (9), or when used in combination with fibrates (10) or possibly niacin (11,12), ezetimibe becomes an attractive choice to use alone or with a statin to achieve lipid targets.…”