Brands, Medical Use, Clinical Data
- Anti-Obesity Agents
- Enzyme Inhibitors
Brands / Synonyms
(-)-Tetrahydrolipstatin; Orlipastat; Orlipastatum [INN-Latin]; Orlistat [USAN:INN]; Tetrahydrolipstatin; Xenical; Xenical
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.
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,  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.
Systemic absorption of orlistat is minimal, however systemic absorption of the drug is not needed for activity.
The results of a massive overdose of Xenical are unknown, although the drug seems relatively harmless.
Biotrnasformation / Drug Metabolism
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).
XENICAL is contraindicated in patients with chronic malabsorption syndrome or cholestasis, and in patients with
known hypersensitivity to XENICAL or to any component of this product.
Alcohol: In a multiple-dose study in 30 normal weight subjects, coadministration of XENICAL and 40
grams of alcohol (e.g., approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics,
orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat.
Cyclosporine: Preliminary data from a XENICAL and cyclosporine drug interaction study indicate a
reduction in cyclosporine plasma levels when XENICAL was coadministered with cyclosporine.
Digoxin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 6 days, XENICAL
did not alter the pharmacokinetics of a single dose of digoxin.
Fat-soluble Vitamin Supplements and Analogues: A pharmacokinetic interaction study showed a 30%
reduction in beta-carotene supplement absorption when concomitantly administered with XENICAL. XENICAL inhibited
absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of
supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time.
Glyburide: In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days,
orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide.
Nifedipine (extended-release tablets): In 17 normal-weight subjects receiving XENICAL 120 mg three
times a day for 6 days, XENICAL did not alter the bioavailability of nifedipine (extended-release tablets).
Oral Contraceptives: In 20 normal-weight female subjects, the treatment of XENICAL 120 mg three
times a day for 23 days resulted in no changes in the ovulation-suppressing action of oral contraceptives.
Phenytoin: In 12 normal-weight subjects receiving XENICAL 120 mg three times a day for 7 days,
XENICAL did not alter the pharmacokinetics of a single 300-mg dose of phenytoin.
Pravastatin: In a 2-way crossover study of 24 normal-weight, mildly hypercholesterolemic patients
receiving XENICAL 120 mg three times a day for 6 days, XENICAL did not affect the pharmacokinetics of
Warfarin: In 12 normal-weight subjects, administration of XENICAL 120 mg three times a day for 16
days did not result in any change in either warfarin pharmacokinetics (both R- and S-enantiomers) or pharmacodynamics
(prothrombin time and serum Factor VII). Although undercarboxylated osteocalcin, a marker of vitamin K nutritional
status, was unaltered with XENICAL administration, vitamin K levels tended to decline in subjects taking XENICAL.
Therefore, as vitamin K absorption may be decreased with XENICAL, patients on chronic stable doses of warfarin who
are prescribed XENICAL should be monitored closely for changes in coagulation parameters.