Orlistat
From Wikipedia, the free encyclopedia
| Image:Orlistat.svg | |
| 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. weight | 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. | |
| Legal status | |
| Routes | Oral |
Orlistat (marketed as Xenical® by Roche), also known as tetrahydrolipstatin, is a drug designed to treat obesity.<ref name="TotalSynth">Bodkin J, Humphries E, McLeod M (2003). "The total synthesis of (-)-tetrahydrolipstatin". Australian Journal of Chemistry 56: 795-803.</ref> 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.<ref name="OriginalSynth">Barbier P, Schneider F (1987). "Synthesis of tetrahydrolipstatin and absolute configuration of tetrahydrolipstatin and lipstatin". Helvetica Chimica Acta 70: 196-202.</ref> However, due to simplicity and stability, orlistat rather than lipstatin was developed into an anti-obesity drug.<ref name="LipstatinSynth">Pommier A, Pons M, Kocienski P (1995). "The first total synthesis of (-)-lipstatin". Journal of Organic Chemistry 60: 7334-7339.</ref>
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.<ref name="PDR"> (2006) 2006 Physicians' Desk Reference (PDR). Thomson PDR. ISBN 1-56363-527-5.</ref>
[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. 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,<ref name="XENDOS">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.</ref> 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. 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. Increased flatulence is also common. Bowel movements may become frequent or urgent. Rare occurrence of fecal incontinence have been seen in clinical trials. To minimize these effects, foods with high fat content should be avoided.
The absorption of fat-soluble vitamins are inhibited by the use of orlistat. A multivitamin tablet containing these vitamins (D, E, A 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 clinicial trial participants, there is evidence to suggest that the introduction of specific varied preparations containing Orlistat can induce cell death in tumor cells and block their growth. <ref name="Menendez et al">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.</ref>
A recent animal study addressed a connection orlistat shares with aberrant crypt foci (ACF) in the colon, which is believed to be one of the earliest precursors of colon cancer.<ref name="Garcia et al">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.</ref>
[edit] Contraindications
Xenical is contraindicated in:
- Malabsorption
- Reduced gallbladder function (e.g. after cholecystectomy)
- Pregnancy and breastfeeding
- Certain kidney problems
[edit] Availability
In most areas orlistat is available by prescription only. However, in Australia it is available over-the-counter in 120 mg size (84 capsules to the pack). No prescription is required unless bought by mail order, in which case a prescription is necessary. Orlistat is classified as 'Pharmacist Only Medicine' in Australia.
On January 23, 2006, a US Food and Drug Administration advisory panel voted 11 to 3 to recommend the approval of an OTC formulation of orlistat (planned to be marketed under the name "Alli" by GlaxoSmithKline).<ref name="WP">"Panel Supports Offering Diet Pill Orlistat Over the Counter", Washington Post, January 24, 2006, pp. A02. Retrieved on 2006-08-10.</ref> The proposed product will consist of 60 mg dosage units, similar to the OTC products available elsewhere. As of November, 2006, the FDA had taken no further action.
