Fat-absorption inhibitors

Orlistat (Xenical /Roche) is a reversible gastric and pancreatic lipase inhibitor. The compound has no effect on appetite suppression but rather acts by inhibiting dietary fat absorption from the GI tract. Sibutramine (Meridia /Abbott) and its major active metabolites are re-uptake... 

Regrettably, the pharmacologist must confess that no drugs exist that can be recommended for the purpose of weight reduction. The so-called appetite suppressants (anorexiants) act only, if at all, for a limited period and are fraught with side effects. Most anorexiants are derivatives of metham-phetamine that have been withdrawn from the market. A different mechanism of action is involved in the case of an inhibitor of pancreatic lipase, which is required in the intestines for fat absorption. This inhibitor (orlistat) diminishes fat absorption so that fats reach the lower bowel, where they can cause disturbances flatulence, steatorrhea, and frequent need to relieve the bowels occur in about 30% of affected subjects. These symptoms correspond exactly to those seen in pancreatic hypofunction which are then usually treated with pancreatic lipase. Before an obese person submits to treatment with orlistat, he or she should voluntarily reduce the food fat content by one half to live free of such unpleasant adverse effects. 

The fat-soluble vitamins (A, D, E, and K) are absorbed dissolved in lipid micelles, and, therefore, absorption will he impaired when the meal is low in fat. Gastrointestinal pathology that results in impaired fat absorption and steattorhea (e.g., untreated celiac disease) will also impair the absorption of fat-soluble vitamins, because they remain dissolved in the unabsorbed Upid in the intestinal lumen. Lipase inhibitors used for the treatment of obesity and fat replacers (e.g., sucrose polyesters such as Olestra ) will similarly impair the absorption of fat-soluble vitamins. 

M. Werder, H. Hauser, S. Abele, D. Seebach, p-Peptides as Inhibitors of Small-Intestinal Cholesterol and Fat Absorption , Helv. Chim. Acta 1999, 82, 1774 - 1783. 

Drugs Drug therapy can reduce fat absorption from the intestine (resins), modify hepatic cholesterol synthesis (HMG-CoA reductase inhibitors), decrease secretion of lipoproteins (niacin), increase peripheral clearance of lipoproteins (fibrates). and can perhaps exert other effects. These drugs are all given orally (Figure 35-1). 

Ezctimibe is a cholesterol absorption inhibitor, and, as the name suggests, it and the major metabolite, ezetimibe glucuronide, impair the intestinal absorption of cholesterol, both from the diet and biliary cholesterol. The absorption of other fats is not affected. Ezetimibe has not been found to have significant effects on cytochrome P450, suggesting it is unlikely to interact by this mechanism. 

The emulsified aliphatic acids form water-soluble dispersions with the bile salts, and pass readily across the frontier of the intestinal mucosa. The glycerol is phosphorylated during its absorb-tion in a manner comparable to the hexoses, and in the cells of the mucosa it recombines with the aliphatic acids to form fat. For this reason, a hormone of the adrenal cortex, in some way associated with phosphorylation, is concerned in fat absorption, and phosphatase-inhibitors, such as phloridzin, retard the absorption process. 

Orlistat is a pancreatic lipase inhibitor used in conjunction with a hypocaloric diet to reduce the absorption of dietary fat in obese patients. Orlistat is administered twice daily immediately before, during or up to 1 hour after each meal. If the meal contains no fat there is no need to take Orlistat. 

Pharmacology Orlistat is a reversible lipase inhibitor for obesity management that acts by inhibiting the absorption of dietary fats. It exerts its therapeutic activity in the lumen of the stomach and small intestine. 

In 1995 the FDA approved saquinavir, the first protease inhibitor, for use in combination with other nucleoside analogue medications. In 1999 a soft gel capsule formulation of saquinavir with considerably improved absorption characteristics was developed. Ritonavir and indinavir have been approved for use alone or in combination with nucleoside analogue medications in people with advanced HIV disease. Nelfinavir is the first protease inhibitor labeled for use in children. Amprenavir is the newest of the protease inhibitors. Amprenavir can be taken with or without food, but it should not be taken with a high-fat meal because the fat content may decrease the absorption of the drug. The most disturbing adverse reactions to protease inhibitors consist of the lipodystrophy syndrome with severe hyperlipidemia and unpredictable fat redistributions over the body... 

Mecfianism of Action A gastric and pancreatic lipase inhibitor that inhibits absorption of dietary fats by inactivating gastric and pancreatic enzymes. Therapeutic Effect Resulting caloric deficit may positively affect weight control. 

Weight loss aids Orlistat, 60 mg with each meal containing fat (not to exceed 180 mg/d) Alii Approved for weight loss in overweight adults > 18 years of age when used in combination with a reduced-calorie, low-fat diet and exercise program. Orlistat is a nonsystemically absorbed inhibitor of gastrointestinal lipase that blocks the absorption of dietary fat. OTC formulation is a half-strength version of the prescription product (Xenical). 

Fernandez, E. and Borgstrom, B. (1989) Effects of tetrahydrolipstatin, a lipase inhibitor, on absorption of fat from the intestine of the rat. Biochim. Biophys. Acta 1001, 249-255. 

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