Gastric and pancreatic lipases are enzymes that play a pivotal role in the digestion of dietary fat. Orlistat, a semisynthetic derivative of lipstatin, is a potent and selective inhibitor of these enzymes. It exerts its effect within the gastrointestinal (Gl) tract. Orlistat acts by binding covalently to the serine residue of the active site of gastric and pancreatic lipases.

When administered with fat-containing foods, orlistat partially inhibits hydrolysis of triglycerides, thus reducing the subsequent absorption of monoacylglycerides and free fatty acids. This effect can be measured using 24h faaecal fat excretion as a representative pharmacodynamic parameter. Orlistat’s Pharmacological activity is dose-dependent and can be described by a simple Emax model which exhibits an initial steep portion of the dose-response curve with a subsequent plateau (approximately 35% inhibition of dietary fat absorption) for doses above 400 mg/d.

At therapeutic doses (120 mg tid with main meals) administered in conjunction with a well balanced, mildly hypocaloric diet, the inhibition of fat absorption (approximately 30% of ingested fat) contributes to an additional caloric deficit of approximately 200 calories. Orlistat does not produce significant disturbances to Gl physiological processes (gastric emptying and acidity, gallbladder motility bile composition and lithogenicity) or to the systemic balance of minerals and electrolytes. Similarly, orlistat does not affect the absorption and pharmacokinetics of drugs with a narrow therapeutic index (phenytoin, warfarin, digoxin) or compounds frequently used by abese patients ( oral contraceptives, glyburide, pravastatin, slow-release nifedipine).

Int J Obes Retal Metab Disord. 1997 Jun:21 Suppl 3:S12-23.


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