Xenical is a potent, specific and long-acting inhibitor of gastrointestinal lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine site of the gastric and pancreatic lipases. The inactivated enzyme is thus unable to hydrolyse dietary fat, in the form of triglycerides, into absorbable free fatty acids and monoglycerides. As undigested triglycerides are not absorbed, the resulting caloric deficit has a positive effect on weight control. Systemic absorption of the drug is therefore not needed for activity.
Efficacy in Patients with Type 2 Diabetes: Pooled data from four 1-year studies and three 6-month studies in type 2 diabetic patients showed that the percentage of responders (≥10% of body weight loss) was 11.3% with orlistat as compared to 4.5% with placebo. The mean difference in weight loss with the drug compared to placebo was 2.47 kg in these patients.
The pooled data from the four 1-year studies and three 6-month studies of Xenical as an adjunct to antidiabetic medications are summarized in the following table: See table.Click on icon to see table/diagram/image
Absorption: Studies in normal weight and obese volunteers have shown that the extent of absorption of orlistat was minimal. Plasma concentrations of intact orlistat were nonmeasurable (<5 ng/mL) 8 hrs following oral administration of orlistat.
In general, at therapeutic doses, detection of intact orlistat in plasma was sporadic and concentrations were extremely low (<10 ng/mL or 0.02 micromole), without evidence of accumulation, and consistent with negligible absorption.
Distribution: The volume of distribution cannot be determined because the drug is minimally absorbed and has no defined systemic pharmacokinetics. In vitro
, orlistat is >99% bound to plasma proteins (lipoproteins and albumin were the major binding proteins). Orlistat minimally partitions into erythrocytes.
Metabolism: Based on animal data, it is likely that the metabolism of orlistat occurs mainly within the gastrointestinal wall. Based on a study in obese patients, of the minute fraction of the dose that was absorbed systemically, 2 major metabolites, M1 (4-member lactone ring hydrolyzed) and M3 (M1, with N-formyl leucine moiety cleaved), accounted for approximately 42% of the total plasma concentration.
M1 and M3 have an open β-lactone ring and extremely weak lipase inhibitory activity (1000- and 2500-fold less than orlistat, respectively). In view of this low inhibitory activity and the low plasma levels at therapeutic doses (average of 26 and 108 ng/mL, respectively), these metabolites are considered to be pharmacologically inconsequential.
Elimination: Studies in normal weight and obese subjects have shown that fecal excretion of the unabsorbed drug was the major route of elimination. Approximately 97% of the administered dose was excreted in feces and 83% of that as unchanged orlistat.
The cumulative renal excretion of total orlistat-related materials was <2% of the given dose. The time to reach complete excretion (fecal plus urinary) was 3-5 days. The disposition of orlistat appeared to be similar between normal weight and obese volunteers. Orlistat, M1 and M3 are all subject to biliary excretion.