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Orlistat
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| Systematic (IUPAC) name | |
| 1-(3-hexyl-4-oxo-oxetan-2-yl)tridecan-2-yl 2-formylamino-4-methyl-pentanoate | |
| Identifiers | |
| CAS number | |
| ATC code | A08 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C29H53NO5 |
| Mol. mass | 495.735 g/mol |
| Pharmacokinetic data | |
| Bioavailability |
Negligible[1] |
| Protein binding | >99% |
| Meta |
In the GI tract |
| Half life | 1 to 2 hours |
| Excretion | Fecal |
| Therapeutic considerations | |
| Licence data |
, |
| Pregnancy cat. |
B1(AU) B(US) |
| Legal status |
Pharmacist Only (S3)(AU) POM(UK) OTC(US) |
| Routes | Oral |
Orlistat (marketed under the trade name Xenical by Roche; or over-the-counter as alli[2] by GlaxoSmithKline (pronounced /ˈælaɪ/, like the English word "ally")—also known as tetrahydrolipstatin—is a drug designed to treat Obesity
Orlistat is the saturated derivative of lipstatin—a potent natural inhibitor of pancreatic lipases isolated from the bacterium Streptomyces toxytricini.[4] However, due to simplicity and stability, orlistat rather than lipstatin was developed into an anti-obesity drug.[5]
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. Only trace amounts of orlistat are absorbed systemically; the primary effect is local lipase inhibition within the GI tract after an oral dose. The primary route of elimination is through the feces.
At the standard prescription dose of 120 mg three times daily before meals, orlistat prevents approximately 30% of dietary fat from being absorbed,[6] and about 25% at the standard over-the-counter dose of 60 mg.[7][8] Higher doses do not produce more potent effects.[9]
The amount of weight loss achieved with orlistat varies. In one-year clinical trials, between 35.5% and 54.8% of subjects achieved a 5% or greater decrease in body mass, although not all of this mass was necessarily fat. Between 16.4% and 24.8% achieved at least a 10% decrease in body mass.[9] After orlistat was stopped, a significant number of subjects regained weight—up to 35% of the weight they had lost.[9] Despite this relatively small body mass effect, the XENDOS study found a 37% reduction in the incidence of type 2 diabetes,[10] a significant difference.
The primary side effects of the drug are gastrointestinal-related, and include steatorrhea—that is, oily, loose stools; because orlistat blocks some of the dietary fat from being absorbed, the fat is excreted unchanged in the feces—, fecal incontinence, frequent or urgent bowel movements, and flatulence. GlaxoSmithKline recommends that Alli users be cautious of the possible side effects until they "have a sense of any treatment effects".[11][12] To minimize these effects, foods with high fat content should be avoided; the manufacturer advises consumers to follow a low-fat, reduced-calorie diet. Oily stools and flatulence can be controlled by reducing the dietary fat content to somewhere in the region of 15 grams per meal.[13]
According to Roche, side effects are most severe when beginning therapy and may decrease in frequency with time;[14] this is supported by the results of the XENDOS study, which found that only 36% of people had gastrointestinal adverse effects during their fourth year of taking orlistat, whereas 91% of study subjects had experienced at least one GI-related side effect during the first year of treatment.[10] It has also been suggested that the decrease in side effects over time may be associated to long-term compliance with a low-fat diet.[15]
The side effect profile of orlistat led US consumer group Prescription Access Litigation (PAL) to award its first 2007 "Bitter Pill Award" to GlaxoSmithKline—the 'With Allies Like This, Who Needs Enemas?' Award.[16][17]
Despite a higher incidence of breast Cancer
A 2006 animal study linked orlistat with aberrant crypt foci (ACF), lesions found in the colon which are believed to be one of the earliest precursors of colon cancer.[21][22]
Absorption of fat-soluble vitamins and other fat-soluble nutrients is inhibited by the use of orlistat. A multivitamin tablet containing vitamins A, D, E, K, and beta-carotene should be taken once a day, at bedtime, when using orlistat.[14]
Orlistat may reduce plasma levels of ciclosporin (also known as "cyclosporin" or "cyclosporine", trade names Sandimmune, Gengraf, Neoral, etc.), an immunosuppressive drug frequently used to prevent transplant rejection; the two drugs should therefore not be administered concomitantly.[14] Orlistat can also impair absorption of the antiarrhythmic amiodarone.[23]
Orlistat is contraindicated in:[14]
In most areas, including the United Kingdom, France, and Canada, orlistat is available by prescription only. In Australia and the United States certain formulations of orlistat have been approved for sale without a prescription.
In Australia, orlistat is currently available over-the-counter in 120 mg size (84 capsules to the pack). Initially available only with a prescription, it was reclassified as a "Pharmacist Only Medicine" in October 2003. In late 2006, the Australian Consumers' Association complained that Roche was inappropriately advertising the drug to teenagers, and Roche was forced to withdraw its ads.[24] The Association filed further complaints[24] with the Therapeutic Goods Administration—TGA, Australia's regulatory authority for healthcare products—and the TGA's Scheduling Committee agreed to convene on February 20, 2007, to discuss possible revoking of orlistat's over-the-counter status.[25] The Committee ultimately decided to keep orlistat as a Schedule 3 drug, but withdrew its authorization of direct-to-consumer Xenical advertising, stating this "increased pressure on pharmacists to provide orlistat to consumers...this in turn had the potential to result in inappropriate patterns of use".[26] Xenical has recently began being advertised direct-to-customers again.
On January 23, 2006, a U.S. Food and Drug Administration
Allī became available in the U.S. in June 2007. It is sold as 60 mg capsules—half the dosage of prescription orlistat.[29][30]
In the EU GSK is currently seeking approval through the European Medicines Agency for the sale of Orlistat over the counter.[31]
As of 2008, no generic formulations of orlistat are legally available in the United States. U.S. patent protection for Xenical, originally to end on June 18, 2004, was extended by five years (until 2009) by the U.S. Patent and Trademark Office. The extension was granted on July 20, 2002.[32]
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