MODE OF ACTION OF ORLISTAT

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, with little or no activity against amylase, trypsin, chymotrypsin and phos pholipases. It exerts its effect within the gastrointestinal (GI) trac t. Orlistat acts by binding covalently to the serine residue of the ac tive site of gastric and pancreatic lipases. When administered with fa t-containing foods, orlistat partially inhibits hydrolysis of triglyce rides, thus reducing the subsequent absorption of monoacylglycerides a nd free fatty acids. This effect can be measured using 24 h faecal fat excretion as a representative pharmacodynamic parameter. Orlistat's p harmacological activity is dose-dependent and can be described by a si mple E-max model which exhibits an initial steep portion of the dose-r esponse curve with a subsequent plateau (similar to 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 (s imilar to 30% of ingested fat) contributes to an additional caloric de ficit of approximately 200 calories. Orlistat does not produce signifi cant disturbances to GI physiological processes (gastric emptying and acidity, gallbladder motility, bile composition and lithogenicity) or to the systemic balance of minerals and electrolytes. Similarly, orlis tat does not affect the absorption and pharmacokinetics of drugs with a narrow therapeutic index (phenytoin, warfarin, digoxin) or compounds frequently used by obese patients (oral contraceptives, glyburide, pr avastatin, slow-release nifedipine).