Pharmacotherapeutic Group: Reversible lipase inhibitor.
Pharmacology: 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. Systemic absorption of drug is therefore not needed for activity. At the recommended therapeutic dose of 120 mg three times a day, orlistat inhibits dietary fat absorption by approximately 30%.
Pharmacokinetics: Systemic exposure to orlistat is minimal. Following oral dosing with 360 mg 14C-orlistat, plasma radioactivity peaked at approximately 8 hours; plasma concentrations of intact orlistat were near the limits of detection (<5 ng/mL). Orlistat is >99% bound to plasma proteins. Orlistat minimally partitioned into erythrocytes. Orlistat is metabolized in two major metabolites, M1 (4-member lactone ring hydrolyzed) and M3 (M1 with N-formyl leucine moiety cleaved). The primary metabolite M1 had a short half life (~3 hours) whereas the secondary metabolite M3 disappeared at a slower rate (half-life ~13.5 hours). 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. The time to reach complete excretion (fecal plus urinary) was 3 to 5 days. Based on limited data, the half-life of the absorbed orlistat is in the range of 1 to 2 hours.