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After confirming its <jats:italic>in vitro<\/jats:italic> potency and relative lack of a major effect on acyl\u2010CoA:cholesterol acyltransferase (ACAT), it was found that this compound lowers plasma cholesterol in cholesterol\u2010fed, but not chow\u2010fed, rats. Measures of liver cholesteryl ester content and the direct determination of cholesterol absorption (lymph\u2010fistula model) show that inhibition of cholesterol absorption is at least one mechanism for the observed cholesterol lowering. However, WAY\u2010121,898 was also active when administered parenterally to cholesterol\u2010fed rats, and in cholesterol\u2010fed hamsters cholesterol\u2010lowering occurred with oral dosing despite no change in cholesterol absorption, suggesting other modes of action possibly relating to inhibition of liver CEH. Combination treatment in cholesterol\u2010fed rats with the ACAT inhibitor CI\u2010976 resulted in a greater\u2010than\u2010additive reduction in plasma cholesterol, imlying that both pCEH and ACAT may play a role in cholesterol absorption in this species. In rabbits, WAY\u2010121,898 prevented the rise in plasma cholesterol due to the feeding of cholesteryl ester but not in rabbits fed (free) cholesterol. In guinea pigs, the compound induced an increase in adrenal cholesteryl ester mass. Taken together, the overall profile in these animal models suggests that WAY\u2010121,898 inhibits more than just the intestinal (lumenal) pCEH, and that the role of this enzyme in cholesterol metabolism may be different within and across species, the former depending upon the dietary cholesterol load.<\/jats:p>","DOI":"10.1007\/s11745-998-0232-8","type":"journal-article","created":{"date-parts":[[2006,11,13]],"date-time":"2006-11-13T13:39:53Z","timestamp":1163425193000},"source":"Crossref","is-referenced-by-count":27,"title":["Lipid\u2010lowering effects of WAY\u2010121,898, an inhibitor of pancreatic cholesteryl ester hydrolase"],"prefix":"10.1002","volume":"33","author":[{"given":"Brian R.","family":"Krause","sequence":"first","affiliation":[{"name":"Department of Vascular &amp; Cardiac Diseases Warner\u2010Lambert Company 2800 Plymouth Rd. 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