Molecule

Drug Groups

approved; investigational

Description

Orlistat is a drug designed to treat obesity. Its primary function is preventing the absorption of fats from the human diet, thereby reducing caloric intake. Orlistat works by inhibiting pancreatic lipase, an enzyme that breaks down triglycerides in the intestine. Without this enzyme, triglycerides from the diet are prevented from being hydrolyzed into absorbable free fatty acids and are excreted undigested.

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.

Toxicity

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

Affected Organisms

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.

Protein Binding

>99% bound to plasma proteins (lipoproteins and albumin were major binding proteins).

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.

References

External Links