Selective cholesterol absorption

Reyderman L, Kosoglou T, Statkevich P, Pember L, Boutros T, Maxwell SE, Affrime M, Batra V. Assessment of a multiple-dose drug interaction between ezetimibe, a novel selective cholesterol absorption inhibitor and gemfibrozil. International J Clin Pharmacol Ther 2004 42(9) 512-8. 

Ballantyne CM. Role of selective cholesterol absorption inhibition in the management of dyslipidemia. Curr Atheroscler Rep. 2004 6 52-59. 

Nutescu EA, Shapiro NL. Ezetitnibe a selective cholesterol absorption inhibitor. Pharmacotherapy. 2003 23 1463-1474. 

Selective cholesterol absorption inhibitor Inhibitors of fasting-induced lipolysis. 

Patrick, J.E. et al., Disposition of the selective cholesterol absorption inhibitor ezetimibe in healthy male subjects, Drug Metab. Dispos., 30(4), 430, 2002. 

Kosoglou T, Meyer I, Veltri EP, Statkevich P, Yang B, Zhu Y, MellarsL, M nvell SE, Patrick JE, Cutler DL, Batra VK, Aflrime MB. Pharmacodynamic interaction between die new selective cholesterol absorption inhibitor ezetimibe and simvastatin. BrJ Clin Pharmacol (2002) 54, 309-19,... 

Patrick, J.E. Kosoglou, T. Stauber, K.L. Alton, K.B. Maxwell, S.E. Zhu, Y. Statkevich, P. lannucci, R. Chowdhury, S. Affrime, M. Cayen, M.N. Disposition of the selective cholesterol absorption inhibitor ezetimibe in healthy male subjects, Drug Metab.Dispos., 2002, 30, 430-437. 

Ezetrol contains ezetimibe, which selectively inhibits absorption of cholesterol in the intestine. It is used as monotherapy or in combination with other drug therapy as an adjunct to lifestyle measures in patients with hypercholesterolaemia. 

Monobactams have been investigated as p-lactamase inhibitors <98CHE1308, 98CHE1319>. The ketene-imine route to P-lactams was used to obtain 1,3,4-trisubstituted derivatives with high trans selectivity. The enolate from 4-hydroxy-y-lactone reacted with the imine (Ar CH NAr ) to give 59, vdiich cyclized in the presence of lithium chloride at low temperature to yield 60. The compounds were assayed for cholesterol absorption inhibition and 61 (R = = OH, R = F) was found to be a potent inhibitor of 3-hydroxy-3-... 

C57BL/6 is the most commonly used strain in cardiovascular research so it is the most characterized with respect to cholesterol absorption and excretion. However, mouse strains do differ with respect to cholesterol absorption (41). Thus, it is very important to have accurate control groups for all absorption experiments. Mice should be matched for age, sex, genetic background, and even diet history (unless that is a parameter being studied). For example, while many investigators will purchase control mice from commercial suppliers or will select them from a wild-type colony or collection, the purist will use control mice from the... 

The mechanism for the inhibition of cholesterol absorption is thought to involve competitive transfer to the micellar phase during absorption from the intestinal lumen. Phytosterols in the micellar phase may also act as emulsifying agents that selectively inhibit the transfer of cholesterol and other lipids (e.g., carotenoids and vitamins) and, thereby, limit their absorption. The exact kinetics governing the sterol competition for transfer are not known, but dietary sterols are absorbed differently in the digestive tract 40-50% for cholesterol, 12-16% for campesterol, 4-5% sitosterol, and <0.5% for phytostanols (37). Before absorption, esterified sterols are hydrolysed effectively in the upper intestine (191). Absorbed phytosterols are excreted by the liver into the bile but are hardly converted to bile acids (192). Numerous studies in animals and humans approved the safety of phytosterols and phytostanols (37). 

Structure of several metabolites, some of which offered advantageous localization to the intestine while others did not [111]. Armed with this knowledge, a second generation compound was designed in which sites of detrimental metabohsm were blocked via strategic incorporation of substituents. The result was ezetimibe (63), a compound which contains hydroxyl functionality crucial to activity and selectivity, as well as fluorine atoms in two key locations which serve to blocked detrimental metabolic pathways without adversely affecting cholesterol absorption inhibitory activity significantly. 

Many studies failed to show any consistent effect of CA on cholesterol absorption[93,95,101]. However, as already mentioned, the feeding of CA alone leads to an increase of both CA and DCA pools. When CA was given together with broad spectrum antibiotics -in order to suppress colonic bacterial flora and so to prevent DCA formation and to achieve a selective expansion of CA pool - a significant increase of cholesterol absorption was observed[98]. 

Selective cholesterol Reduction of LDL absorption inhibitor cholesterol levels by mp 16S °C inhibiting dietary... 

Ezetimibe (Zetia) is a selective inhibitor of dietary cholesterol absorption. In addition to this decreased cholesterol absorption leads to an increase in LDL-cholesterol uptake into cells, thus decreasing levels in the blood plasma (Rossi S, 2006). 

Miettinen, TA, Tilvis, RS and Kesaniemi, YA (1990) Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of arandomly selected male population. Am. J. Epidemiol., 131, 20-31. 

Catapano AL. Ezetimibe a selective inhibitor of cholesterol absorption. > . Heart J. Suppl. 2001 3(Esuppl) E6-E10. 

Ezetimibe is a selective inhibitor of intestinal absorption of cholesterol and phytosterols. A transport protein, NPC1L1, appears to be the target of the drug. It is effective even in the absence of dietary cholesterol because it inhibits reabsorption of cholesterol excreted in the bile. 

Ezetimibe is a selective potent inhibitor of the intestinal absorption of dietary and biliary cholesterol. A total of 432 patients were included in a pooled analysis of two phase-II studies, both lasting for 12 weeks ezetimibe was well tolerated, with an adverse events profile similar to that of placebo (1). In 668 patients who took ezetimibe with simvastatin, the adverse effects were similar to those with simvastatin alone (2). 

Pancreatic cholesterol esterase (3.1.1.3.) aids in transporting cholesterol to the enterocyte. By utilizing a selective and potent cholesterol esterase inhibitor 6-chloro-3-(l-ethyl-2-cyclohexyl)-2-pyrone, the absorption of cholesterol in hamsters could be reduced [71]. Wadkins et al. [72] synthesized novel sulfonamide derivatives, which demonstrated greater than 200-fold selectivity for human intestinal carboxylesterase compared with the human liver carboxylesterase hCEl, and none of them was an inhibitor of human acetylcholinesterase or butyrylcholinester-ase. Maybe these agents can serve as lead compounds for the development of effective, selective carboxylesterase inhibitors for clinical applications. Also the potent P-gp inhibitor verapamil [73] as well as S,S,S-tributylphosphortrithionate (DEF) [74] may exhibit carboxylesterase inhibitory properties. Various other inhibitors of human esterases are listed in Table 5.6. 

Benecol is a brand of margarine invented by a small Finnish food company (The Raisio Group). Research published in the New England Journal of Medicine by Finnish researchers indicates that regular use of Benecol can lower blood cholesterol levels by an average of 10 percent in a randomly selected, mildly hypercholesterolemic population sample. Its active ingredient is a plant sterol from Nordic pine trees known as beta-sitostanol, which apparently can block some of the body s absorption of dietary cholesterol. At present, 5 tons of wood waste are processed to produce 1 pound of the oil that is the source of the sterol. 

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