Orlistat

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Orlistat
Systematic (IUPAC) name
(S)-((S)-1-((2S,3S)-3-hexyl-4-oxooxetan-2-yl)tridecan-2-yl) 2-formamido-4-methylpentanoate
Identifiers
CAS number 96829-58-2
ATC code A08AB01
PubChem 3034010
DrugBank APRD00255
ChemSpider 2298564
Chemical data
Formula C29H53NO5 
Mol. mass 495.735 g/mol
Pharmacokinetic data
Bioavailability Negligible[1]
Protein binding >99%
Metabolism In the GI tract
Half life 1 to 2 hours
Excretion Fecal
Therapeutic considerations
Licence data

EU EMEA:link, US FDA:link
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.[3] 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—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]

Contents

[edit] Pharmacology

Orlistat works by inhibiting gastrointestinal 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]

[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, 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.

[edit] Side effects

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]

[edit] Long-term

Despite a higher incidence of breast cancer amongst those taking orlistat in early, pooled clinical trial data—the analysis of which delayed FDA review of orlistat[18]—a two-year study published in 1999 found similar rates between orlistat and placebo (0.54 versus 0.51%), and evidence that tumors predated treatment in 3 of the 4 participants who had them.[19] There is evidence from an in vitro study to suggest that the introduction of specific varied preparations containing orlistat, namely the concurrent administration of orlistat and the monoclonal antibody trastuzumab, can actually induce cell death in breast cancer cells and block their growth.[20]

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]

[edit] Precautions

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]

[edit] Interactions

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]

[edit] Contraindications

Orlistat is contraindicated in:[14]

[edit] Availability

Orlistat has historically been available by prescription only, and this situation continues in Canada. In Australia, the European Union,[24] and the United States, certain formulations of orlistat have been approved for sale without a prescription.

[edit] Australia & New Zealand

In Australia and New Zealand, 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.[25] The Association filed further complaints[25] 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.[26] 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".[27] Xenical has recently began being advertised direct-to-customers again.

[edit] United States

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.[28] Approval was granted on February 7, 2007,[29] and alli became the first weight loss drug officially sanctioned by the U.S. government for over-the-counter use.[30] 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.[31]

Alli became available in the U.S. in June 2007. It is sold as 60 mg capsules—half the dosage of prescription orlistat.[30][31]

[edit] European Union

On January 21, 2009, the European Medicines Agency granted approval for the sale of orlistat without a prescription.[32][24]

[edit] Generic formulations

As of 2009, 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.[33]

[edit] References

  1. ^ Zhi J, Melia AT, Eggers H, Joly R, Patel IH (1995). "Review of limited systemic absorption of orlistat, a lipase inhibitor, in healthy human volunteers". J Clin Pharmacol 35 (11): 1103–8. PMID 8626884. 
  2. ^ Always rendered with a lowercase a, i.e. as alli.
  3. ^ Bodkin J, Humphries E, McLeod M (2003). "The total synthesis of (−)-tetrahydrolipstatin". Australian Journal of Chemistry 56 (8): 795–803. doi:10.1071/CH03121. 
  4. ^ Barbier P, Schneider F (1987). "Syntheses of tetrahydrolipstatin and absolute configuration of tetrahydrolipstatin and lipstatin". Helvetica Chimica Acta 70 (1): 196–202. doi:10.1002/hlca.19870700124. 
  5. ^ Pommier A, Pons M, Kocienski P (1995). "The first total synthesis of (-)-lipstatin". Journal of Organic Chemistry 60 (22): 7334–7339. doi:10.1021/jo00127a045. 
  6. ^ 2006 Physicians' Desk Reference (PDR). Thomson PDR. 2006. ISBN 1-56363-527-5. 
  7. ^ "myalli.com – frequently asked questions". GlaxoSmithKline. 2007. http://www.myalli.com/whatisalli/commonquestions.aspx. Retrieved on 2007-08-18. 
  8. ^ Parker-Pope, Tara. "Weighing the Pros and Cons Of New Fat-Blocking Drug Alli", The Wall Street Journal, June 19, 2007, pp. D1. Retrieved on 2007-08-18.
  9. ^ a b c "Xenical Pharmacology, Pharmacokinetics, Studies, Metabolism". RxList.com. 2007. http://www.rxlist.com/cgi/generic/orlistat_cp.htm. Retrieved on 2007-03-16. 
  10. ^ a b 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. doi:10.2337/diacare.27.1.155. PMID 14693982. http://care.diabetesjournals.org/cgi/content/full/27/1/155. 
  11. ^ "myalli.com – what are treatment effects?". http://www.myalli.com/howdoesitwork/treatmenteffects.aspx. Retrieved on 2007-06-24. 
  12. ^ Hall, Carla (June 15, 2007). "New diet drug touches off a feeding frenzy". Los Angeles Times. http://www.latimes.com/news/science/la-me-diet15jun15,0,3267551.story?coll=la-home-center. Retrieved on 2007-06-20. 
  13. ^ PRNewswire (February 7, 2007) (PDF, 21 KiB). FDA Approves alli (orlistat 60 mg capsules) Over-The-Counter. Press release. http://www.bumc.bu.edu/www/bumc/coc/pdfs/ApovianFDA.pdf. Retrieved on 2007-04-08. 
  14. ^ a b c d Roche Pharmaceuticals (January 5, 2007). "Xenical Product Label" (PDF, 300 KiB). U.S. Food and Drug Administration. http://www.fda.gov/cder/foi/label/2007/020766s022lbl.pdf. Retrieved on 2007-02-19. 
  15. ^ Mancini MC, Halpern A (2006). "Pharmacological treatment of obesity". Arq Bras Endocrinol Metab 50 (2): 377–89. doi:10.1590/S0004-27302006000200024. PMID 16767304.  Free full text with registration
  16. ^ Cohen, Deborah (September 25, 2007). "A bitter pill for slimmers?". The Guardian. http://www.guardian.co.uk/health/story/0,,2176582,00.html. Retrieved on 2009-01-22. 
  17. ^ Prescription Access Litigation (June 7, 2007). PAL Announces First Bitter Pill Award of 2007 to GlaxoSmithKline: 'With Allies Like This, Who Needs Enemas?’ Award. Press release. http://www.prescriptionaccess.org/press/pressreleases?id=0041. Retrieved on 2009-01-22. 
  18. ^ Kolata, Gina (January 20, 1999). "Obesity Drug Can Lead to Modest Weight Loss, Study Finds". The New York Times. http://query.nytimes.com/gst/fullpage.html?res=9A0CE2DD1230F933A15752C0A96F958260&sec=&spon=&pagewanted=all. Retrieved on 2007-12-11. 
  19. ^ Davidson MH, Hauptman J, DiGirolamo M, et al. (1999). "Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial". JAMA 281 (3): 235–42. doi:10.1001/jama.281.3.235. PMID 9918478. 
  20. ^ 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. doi:10.1093/annonc/mdi239. PMID 15870086. 
  21. ^ 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. doi:10.1016/j.canlet.2005.09.011. PMID 16377080. 
  22. ^ Takayama T, Katsuki S, Takahashi Y, Ohi M, Nojiri S, Sakamaki S, Kato J, Kogawa K, Miyake H, Niitsu Y (1998). "Aberrant crypt foci of the colon as precursors of adenoma and cancer". N Engl J Med 339 (18): 1277–84. doi:10.1056/NEJM199810293391803. PMID 9791143.  Free full text with registration.
  23. ^ Zhi J, Moore R, Kanitra L, Mulligan TE (2003). "Effects of orlistat, a lipase inhibitor, on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin) in healthy volunteers". J Clin Pharmacol 43 (4): 428–35. doi:10.1177/0091270003252236. PMID 12723464. 
  24. ^ a b "Chemists to provide obesity pill". BBC News. January 21, 2009. http://news.bbc.co.uk/1/hi/health/7843061.stm. Retrieved on 2009-01-22. 
  25. ^ a b "Drug advertising: Xenical". CHOICE. February 2007. http://www.choice.com.au/viewArticle.aspx?id=104825&catId=100386&tid=100008&p=2&title=Drug+advertising. Retrieved on 2007-02-16. 
  26. ^ Bissett, Kelvin (February 5, 2007). "Weight drugs danger revealed". The Daily Telegraph. http://www.news.com.au/dailytelegraph/story/0,22049,21170905-5006009,00.html. Retrieved on 2007-02-16. 
  27. ^ Australian Therapeutic Goods Administration (February 22, 2007). Scheduling of orlistat. Press release. http://www.tga.gov.au/media/2007/070222-orlistat.htm. Retrieved on 2007-03-03. 
  28. ^ "Panel Supports Offering Diet Pill Orlistat Over the Counter". The Washington Post: pp. A02. January 24, 2006. http://www.washingtonpost.com/wp-dyn/content/article/2006/01/23/AR2006012301507.html. Retrieved on 2006-08-10. 
  29. ^ U.S. Food and Drug Administration (February 7, 2007). FDA Approves Orlistat for Over-the-Counter Use. Press release. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01557.html. Retrieved on 2007-02-07. 
  30. ^ a b Saul, Stephanie (February 7, 2007). "Weight-Loss Drug to Be Sold Over the Counter". The New York Times. http://www.nytimes.com/2007/02/07/health/07cnd-diet.html. Retrieved on 2007-02-10. 
  31. ^ a b Schmid, Randolph E (February 8, 2007). "FDA OKs First Nonprescription Diet Pill". The Washington Post. http://www.washingtonpost.com/wp-dyn/content/article/2007/02/08/AR2007020800114.html. Retrieved on 2007-02-10. 
  32. ^ GlaxoSmithKline (January 21, 2009). GlaxoSmithKline receives European Commission approval to market alli® (orlistat 60mg). Press release. http://www.gsk.com/media/pressreleases/2009/2009_pressrelease_10011.htm. Retrieved on 2009-01-22. 
  33. ^ Rogan, James E. (July 30, 2002). "Certificate Extending Patent Term Under 35 U.S.C. § 156" (PDF, 32 KiB). United States Patent and Trademark Office. http://www.uspto.gov/web/offices/pac/dapp/opla/term/certs/4598089.pdf. Retrieved on 2007-04-08. 

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