Orlistat - Xenical
Orlistat - (Xenical®)
Classification:
Description: Orlistat is a gastrointestinal lipase inhibitor indicated for obesity management, including weight loss and weight maintenance, when used in conjunction with a reduced-calorie diet. The first in a new class of drugs, orlistat works non-systemically to block the absorption of dietary fat. Even though orlistat was placed on a fast-track by the FDA, final approval was delayed when results of clinical trials suggested a higher incidence of breast cancer in the orlistat group compared to placebo. Based on orlistat’s minimal systemic absorption, lack of an estrogen-stimulating effect in women, and evidence of tumor preexistence at randomization, investigators concluded that no biological association between orlistat and breast cancer exists. Orlistat was approved for use in Europe in July, 1998. The FDA granted approval of orlistat for adults on April 26, 1999. On December 15, 2003 the FDA approved orlistat for use in obese adolescents 12 to 16 years of age.
Mechanism of Action: Orlistat produces weight loss through inhibition of nutrient absorption. A covalent bond is formed with the active serine residue site of gastric and pancreatic lipases within the lumen of the stomach and the small intestine. As these enzymes become unavailable to hydrolyze dietary triglycerides into free fatty acids and monoglycerides, less fat is absorbed by the body. This results in decreased caloric intake that may result in negative energy balance and weight loss. Therefore, systemic absorption of the drug is not needed to produce a weight-lowering effect. At the recommended therapeutic dose of 120 mg orlistat PO three times per day, dietary fat absorption is inhibited by approximately 30%.
Chemical Structure For: Orlistat
Pharmacokinetics: Orlistat is administered orally and has minimal systemic absorption. Peak plasma concentrations of orlistat (<5 ng/ml) occurred approximately 8 hours after a 360 mg dose. Sporadic intact amounts of orlistat, low plasma concentration levels (<10 ng/ml), and no evidence of accumulation were observed during therapeutic studies. Based on fecal fat measurements, the effect of orlistat may be seen within 24 to 48 hours. In vitro, orlistat was > 99% bound to plasma proteins (primarily lipoproteins and albumin) with minimal partitioning into erythrocytes. Metabolism of orlistat to weakly active and inactive metabolites is believed to occur mainly within the gastrointestinal wall. Approximately 83% of a single oral dose of orlistat was excreted unchanged in the feces. Renal excretion was < 2% of the dose. Complete excretion of both urinary and fecal orlistat was reached in 3 to 5 days. The estimated half-life of the absorbed portion of orlistat was approximately 1 to 2 hours.
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