Orlistat

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Orlistat
Systematic (IUPAC) name
1-(3-hexyl-4-oxo-oxetan-2-yl)tridecan-2-yl 2-formylamino-4-methyl-pentanoate
Identifiers
CAS number 96829-58-2
ATC code A08AB01
PubChem 3034010
DrugBank APRD00255
Chemical data
Formula C29H53NO5 
Mol. mass 495.735 g/mol
Pharmacokinetic data
Bioavailability Negligible
Protein binding >99%
Metabolism In the GI tract
Half life 1 to 2 hours
Excretion Fecal
Therapeutic considerations
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 by GlaxoSmithKline), also known as tetrahydrolipstatin, is a drug designed to treat obesity.[1] Its primary function is preventing the absorption of fats from the human diet, thereby reducing caloric intake. It is intended for use in conjunction with a physician-supervised reduced calorie diet.

Orlistat is the saturated derivative of lipstatin. Lipstatin was isolated from Streptomyces toxytricini and is also a potent inhibitor of pancreatic lipases.[2] However, due to simplicity and stability, orlistat rather than lipstatin was developed into an anti-obesity drug.[3]

Contents

[edit] Pharmacology

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.[4]

[edit] Efficacy

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,[5] although not all of this mass was necessarily fat. Between 16.4% and 24.8% achieved at least a 10% decrease in body mass.[5] A significant number of subjects regained the weight after they stopped using orlistat. Despite this relatively small body mass effect, there was a 37% reduction in the incidence of Type 2 diabetes,[6] a significant difference.

[edit] Side effects

The primary side effects of the drug are gastrointestinal-related. Side effects are most severe within the first year of therapy, and decrease in frequency with time.[7] Because orlistat's main effect is to prevent dietary fat from being absorbed, the fat is excreted unchanged in the feces and so the stool may become oily or loose (steatorrhea). Increased flatulence is also common. Bowel movements may become frequent or urgent, and rare occurrences of fecal incontinence have been seen in clinical trials. To minimize these effects, foods with high fat content should be avoided and 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.[8]

The absorption of fat-soluble vitamins and other fat-soluble nutrients are inhibited by the use of orlistat. A multivitamin tablet containing these vitamins (A, D, E, K, and beta-carotene) should be taken once a day, at least 2 hours before or after taking the drug.

Despite claims that orlistat increases the risk of breast cancer amongst clinical trial participants, there is evidence to suggest that the introduction of specific varied preparations containing orlistat can actually induce cell death in tumor cells and block their growth.[9]

A 2006 animal study addressed a connection orlistat shares with aberrant crypt foci (ACF) in the colon, which are believed to be one of the earliest precursors of colon cancer.[10]

[edit] Contraindications

Xenical is contraindicated in:

[edit] Availability

In most areas orlistat is available by prescription only. However, in Australia it is currently available over-the-counter in 120 mg size (84 capsules to the pack). Initially available only with a prescription, orlistat was reclassified as a "Pharmacist Only Medicine" in October 2003. In late 2006, the Australian Consumers' Association complained that Roche were inappropriately advertising the drug to teenagers, and Roche was forced to withdraw its ads.[11] The Association filed further complaints[11] 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.[12] 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".[13]

On January 23, 2006, a U.S. Food and Drug Administration advisory panel voted 11 to 3 to recommend the approval of an OTC formulation of orlistat, to be marketed under the name alli by GlaxoSmithKline.[14] Approval was granted on February 7, 2007,[15] and alli became the first weight loss drug officially sanctioned by the U.S. government for over-the-counter use.[16] Consumer advocacy organization Public Citizen, through its Health Research Group, opposed over-the-counter approval for orlistat, calling it "the height of recklessness" and "a dangerous mistake" due to questionable benefits and possible adverse effects.[17]

alli will be sold as 60 mg capsules, half the dosage of prescription orlistat, and will be made available in the U.S. during summer 2007.[16][17]

[edit] References

  1. ^ Bodkin J, Humphries E, McLeod M (2003). "The total synthesis of (-)-tetrahydrolipstatin". Australian Journal of Chemistry 56: 795-803. 
  2. ^ Barbier P, Schneider F (1987). "Synthesis of tetrahydrolipstatin and absolute configuration of tetrahydrolipstatin and lipstatin". Helvetica Chimica Acta 70: 196-202. 
  3. ^ Pommier A, Pons M, Kocienski P (1995). "The first total synthesis of (-)-lipstatin". Journal of Organic Chemistry 60: 7334-7339. 
  4. ^ (2006) 2006 Physicians' Desk Reference (PDR). Thomson PDR. ISBN 1-56363-527-5. 
  5. ^ a b Xenical Pharmacology, Pharmacokinetics, Studies, Metabolism. RxList.com (2007). Retrieved on 2007-03-16.
  6. ^ Torgerson J, Hauptman J, Boldrin M, Sjöström L (2004). "XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients.". Diabetes Care 27 (1): 155-61. PMID 14693982. 
  7. ^ Roche Pharmaceuticals (January 5, 2007). Xenical® Product Label (PDF, 300 KiB). U.S. Food and Drug Administration. Retrieved on 2007-02-19.
  8. ^ Alli Pills Side Effects. Alli Pills Site (March 2007). Retrieved on 2007-03-13.
  9. ^ J. A. Menendez, L. Vellon and R. Lupu (2005). "Antitumoral actions of the anti-obesity drug orlistat (XenicalTM) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene". Annals of Oncology 16 (8): 1253–1267. PMID 15870086. 
  10. ^ Garcia S, da Costa Barros L, Turatti A, Martinello F, Modiano P, Ribeiro-Silva A, de Oliveira Vespúcio M, Uyemura S (2006). "The anti-obesity agent Orlistat is associated to increase in colonic preneoplastic markers in rats treated with a chemical carcinogen.". Cancer Lett 240 (2): 221–4. PMID 16377080. 
  11. ^ a b Drug advertising: Xenical. CHOICE (February 2007). Retrieved on 2007-02-16.
  12. ^ Bissett, Kelvin. "Weight drugs danger revealed", The Daily Telegraph, February 5, 2007. Retrieved on 2007-02-16.
  13. ^ Australian Therapeutic Goods Administration (February 22, 2007). Scheduling of orlistat. Press release. Retrieved on 2007-03-03.
  14. ^ "Panel Supports Offering Diet Pill Orlistat Over the Counter", The Washington Post, January 24, 2006, pp. A02. Retrieved on 2006-08-10.
  15. ^ U.S. Food and Drug Administration (February 7, 2007). FDA Approves Orlistat for Over-the-Counter Use. Press release. Retrieved on 2007-02-07.
  16. ^ a b Saul, Stephanie. "Weight-Loss Drug to Be Sold Over the Counter", The New York Times, February 7, 2007. Retrieved on 2007-02-10.
  17. ^ a b Schmid, Randolph E. "FDA OKs First Nonprescription Diet Pill", The Washington Post, February 8, 2007. Retrieved on 2007-02-10.

[edit] External links

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