indication

For obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. Also used to reduce the risk for weight regain after prior weight loss. Use of orlistat is pending revision due to reports of liver-related adverse events.

pharmacology

Orlistat is a lipase inhibitor for obesity management that acts by inhibiting the absorption of dietary fats. At the recommended therapeutic dose of 120 mg three times a day, orlistat inhibits dietary fat absorption by approximately 30%. It works by inhibiting pancreatic lipase, an enzyme that breaks down fat in the intestine. Without this enzyme, fat from the diet is excreted undigested and not absorbed by the body. Because some vitamins are fat soluble, the effect of orlistat is to reduce their body absorption. Therefore the drug should only be taken in conjuction with fatty meals, and a multivitamin tablet containing these vitamins (D E K and beta-carotene) should be taken once a day, at least 2 hours before or after taking the drug. In the March 15, 2004 issue of Cancer Research, [1] Steven J. Kridel et al. state that orlistat may also inhibit growth of prostate cancer, and in theory may be useful in treating other cancers, by interfering with the metabolism of fats.

mechanism of action

Orlistat is a reversible inhibitor of lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine residue site of gastric and pancreatic lipases. The inactivated enzymes are thus unavailable to hydrolyze dietary fat in the form of triglycerides into absorbable free fatty acids and monoglycerides. As undigested triglycerides are not absorbed, the resulting caloric deficit may have a positive effect on weight control.

toxicity

The results of a massive overdose of Xenical are unknown, although the drug seems relatively harmless.

biotransformation

Metabolized primarily within the gastrointestinal wall forming relatively inactive metabolites. Metabolites M1 (4-member lactone ring hydrolyzed) and M3 (M1 with N-formyl leucine moiety cleaved) accounted for approximately 42% of total radioactivity in plasma. M1 and M3 have an open beta-lactone ring and extremely weak lipase inhibitory activity (1000- and 2500-fold less than orlistat, respectively).

absorption

Systemic absorption of orlistat is minimal, however systemic absorption of the drug is not needed for activity.

half life

1 to 2 hours.

route of elimination

Following a single oral dose of 360 mg 14C-orlistat in both normal weight and obese subjects, fecal excretion of the unabsorbed drug was found to be the major route of elimination. Orlistat and its M1 and M3 metabolites were also subject to biliary excretion.

drug interactions

Acenocoumarol: Orlistat may increase the anticoagulant effect of acenocoumarol.

Anisindione: Orlistat may increase the anticoagulant effect of anisindione.

Calcipotriol: Orlistat may decrease the serum concentration of fat soluble vitamins like vitamin D. Hence, this applies to calcipotriol, a synthetic derivative of vitamin D. Administer oral fat soluble vitamins at least 2 hours before or after the administration of orlistat. Avoid concomitant administration due to the risk of impaired vitamin absorption. Similar precautions do not apply to parenterally administered fat soluble vitamins.

Cholecalciferol: Orlistat may decrease the serum concentration of Vitamin D analogs. More specifically, orlistat may impair absorption of Vitamin D analogs such as cholecalciferol. Monitor clinical response (plasma calcium concentrations) to orally administered vitamin D analogs closely if used with orlistat. When this combination must be used, consider administering the vitamin D analog at least 2 hours before or after the administration of orlistat.

Cyclosporine: Orlistat decreases the effect of cyclosporine

Dicumarol: Orlistat may increase the anticoagulant effect of dicumarol.

Vitamin A: Orlistat may impair the absorption of vitamin A, a fat soluble vitamin. Oral vitamin A should be administered 2 hours prior to or post orlistat administration.

Vitamin E: Orlistat may impair the absorption of vitamin E, a fat soluble vitamin. Oral vitamin E should be administered 2 hours prior to or post orlistat administration.

Warfarin: Orlistat may increase the anticoagulant effect of warfarin.