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. 2000 Apr;129(8):1748-54.
doi: 10.1038/sj.bjp.0703235.

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

M van Heek  1 , C Farley, D S Compton, L Hoos, K B Alton, E J Sybertz, H R Davis Jr
Affiliations

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

M van Heek et al. Br J Pharmacol. 2000 Apr.

Abstract

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. To understand the increased potency of the glucuronide, the metabolism and distribution of SCH58235 and SCH60663 were studied in bile duct-cannulated rats. One minute after intraduodenal delivery of SCH58235, significant levels of compound were detected in portal plasma; >95% 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, >95% of the compound remained in the intestinal lumen and wall, which may explain its increased potency. Significant 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. 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(-1)) and rhesus monkey (ID(50) = 0.0005 mg kg(-1)).

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Figures

Figure 1
Figure 1
HPLC chromatogram and chemical structures. HPLC chromatogram of Schering-Plough reference compounds SCH58235 and its phenolic glucuronide, SCH60663 (UV detector). The 3H-metabolite from an extract of bile from rats dosed with 3H-SCH58235 (radiometric detector) reveals a single peak which co-elutes with SCH60663.
Figure 2
Figure 2
Determination of cholesterol absorption inhibitory activity of SCH58235 vs SCH60663 in the bile duct-cannulated rat. Inhibition of 14C-cholesterol appearance in plasma of bile duct-cannulated rats after intraduodenal delivery of control bile (control) or SCH58235 or SCH60663 in bile at the doses indicated, followed by an intraduodenal bolus delivery of an emulsion containing 14C-cholesterol. Values are mean±s.e.mean, n=5 per group.
Figure 3
Figure 3
Time-course of 3H compounds in portal plasma and bile after intraduodenal delivery of 3H-SCH58235. 3H-SCH58235 was delivered directly into the intestines of bile duct-cannulated rats and portal plasma was taken at the indicated time after dosing. Each time-point constitutes a separate group of animals. Values are mean±s.e.mean, n=4 per group.
Figure 4
Figure 4
Time course of tissue distribution of 3H-SCH58235 vs 3H-SCH58235-glucuronide (3H-SCH60663) in bile duct-cannulated rats. Distribution of 3H-compound after intraduodenal dosing of 3H-SCH58235 (left panels) or 3H-SCH60663 (right panels) after 7 min (top panels), 60 min (middle panels) or 120 min (bottom panels). Each treatment and time-point constitutes one group of rats. Values are mean±s.e.mean, n=4 per group.
Figure 5
Figure 5
Effect on cholesterol absorption of intravenously administered SCH58235 in intact vs bile duct-cannulated rats. Inhibition of 14C-cholesterol appearance in plasma (A) or liver (B) of intact or bile duct-cannulated rats after intravenous delivery of control plasma (control) or SCH58235 in plasma at 0.3 mg kg−1, followed by an intraduodenal bolus delivery of an emulsion containing 14C-cholesterol. Cholesterol absorption was allowed to take place for 3 h after dosing. Percentages refer to the per cent change from the appropriate control group. Values are mean±s.e.mean, n=5 per group.
Figure 6
Figure 6
Distribution of 3H compound in the intestinal wall after intravenously administered SCH58235 in intact and bile duct-cannulated rats. Distribution of 3H compound in intestinal lumen, intestinal wall, plasma, liver, and bile 3 h after intravenous dosing of 3H-SCH58235 in intact or bile duct-cannulated rats. Values are mean±s.e.mean, n=5 per group.
Figure 7
Figure 7
Autoradiographic analysis of intestinal wall after intravenous administration of 3H-SCH58235 in bile duct-cannulated rats. Localization of 3H compound in the intestinal villi 3 h after an intravenous dose of 3H-SCH58235. Three distinct villi can be seen. The dark background is the intestinal lumen. The emulsion autoradiogram demonstrates that the 3H compound (white grains) concentrates on the surface of the enterocytes at the tips of the villi (dark field microscopy, original magnification 250×).
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