Orlistat

Last updated

Orlistat
Orlistat structure.svg
Orlistat ball-and-stick model.png
Clinical data
Trade names Xenical, Alli
Other namestetrahydrolipstatin
AHFS/Drugs.com Monograph
MedlinePlus a601244
License data
Pregnancy
category
  • AU:B1
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Negligible [8]
Protein binding >99%
Metabolism In the GI tract
Elimination half-life 1 to 2 hours
Excretion Fecal
Identifiers
  • (S)-((S)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl) 2-formamido-4-methylpentanoate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.167.400 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C29H53NO5
Molar mass 495.745 g·mol−1
3D model (JSmol)
  • O=C(O[C@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)CCCCCCCCCCC)[C@@H](NC=O)CC(C)C
  • InChI=1S/C29H53NO5/c1-5-7-9-11-12-13-14-15-16-18-24(34-29(33)26(30-22-31)20-23(3)4)21-27-25(28(32)35-27)19-17-10-8-6-2/h22-27H,5-21H2,1-4H3,(H,30,31)/t24-,25-,26-,27-/m0/s1 Yes check.svgY
  • Key:AHLBNYSZXLDEJQ-FWEHEUNISA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Orlistat, sold under the brand name Xenical among others, is a medication used to treat obesity. Its primary function is preventing the absorption of fats from the human diet by acting as a lipase inhibitor, thereby reducing caloric intake. It is intended for use in conjunction with a healthcare provider-supervised reduced-calorie diet. [4]

Contents

Orlistat is the saturated derivative of lipstatin, a potent natural inhibitor of pancreatic lipases isolated from the bacterium Streptomyces toxytricini . [9] However, due to its relative simplicity and stability, orlistat was chosen over lipstatin for development as an anti-obesity drug. [10]

The effectiveness of orlistat in promoting weight loss is definite but modest. Pooled data from clinical trials suggest that people given orlistat in addition to lifestyle modifications, such as diet and exercise, lose about 2–3 kilograms (4–7 lb) more than those not taking the drug over the course of a year. [11] Orlistat also modestly reduces blood pressure and appears to prevent the onset of type 2 diabetes, whether from the weight loss itself or other effects. It reduces the incidence of diabetes type II in people who are obese around the same amount that lifestyle changes do. [12]

Benefits aside, however, orlistat is noted for its gastrointestinal side effects (sometimes referred to as treatment effects), which can include steatorrhea (oily, loose stools). They decrease with time, however, and are the most frequently reported adverse effects of the drug. [4] In Australia, the United States and the European Union, orlistat is available for sale without a prescription. [13] Over-the-counter approval was controversial in the United States, with consumer advocacy group Public Citizen repeatedly opposing it on safety and efficacy grounds. [14] Generic formulations of orlistat are available in some countries. In Australia it has been listed as an S3 medication, available from a pharmacist without a prescription, since 2000. [15]

Medical uses

Orlistat is used for the treatment of obesity. 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 fat. [4] After orlistat was stopped, a significant number of subjects regained weight—up to 35% of the weight they had lost. [4] It reduces the incidence of diabetes type II in people who are obese around the same amount that lifestyle changes do. [12] Long-term use of orlistat also leads to a very modest reduction in blood pressure (mean reductions of 2.5 and 1.9 mmHg in systolic and diastolic blood pressure respectively). [16]

Contraindications

Orlistat is contraindicated in: [4]

Side effects

The primary side effects of the drug are gastrointestinal-related, and include steatorrhea (oily, loose stools with excessive flatus due to unabsorbed fats reaching the large intestine), fecal incontinence and frequent or urgent bowel movements. [17] 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. [18] The manual for Alli makes it clear that orlistat treatment involves aversion therapy, encouraging the user to associate eating fat with unpleasant treatment effects. [19]

Side effects are most severe when beginning therapy and may decrease in frequency with time; [4] It has also been suggested that the decrease in side effects over time may be associated with long-term compliance with a low-fat diet. [20]

On 26 May 2010, the U.S. Food and Drug Administration (FDA) approved a revised label for Xenical to include new safety information about cases of severe liver injury that have been reported rarely with the use of this medication. [21]

An analysis of over 900 orlistat users in Ontario showed that their rate of acute kidney injury was more than triple that of non-users. [22]

A study from 2013 looked at 94,695 participants receiving orlistat in the UK between 1999 and 2011. [23] The study showed no evidence of an increased risk of liver injury during treatment. [23] They concluded: [23]

The incidence of acute liver injury was higher in the periods both immediately before and immediately after the start of orlistat treatment. This suggests that the observed increased risks of liver injury linked to the start of treatment may reflect changes in health status associated with the decision to begin treatment rather than any causal effect of the drug.

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 [24] —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. [25] 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 induce cell death in breast cancer cells and block their growth. [26]

Fecal fat excretion promotes colon carcinogenesis. In 2006 the results of 30-day study were published indicating that orlistat at a dosage of 200 mg/kg chow administered to rats consuming a high-fat chow and receiving two 25 mg/kg doses of the potent carcinogen 1,2-dimethylhydrazine produced significantly higher numbers of aberrant crypt foci (ACF) colon lesions than did the carcinogen plus high-fat chow without orlistat. [27] ACF lesions are believed to be one of the earliest precursors of colon cancer. [28]

Precautions

Absorption of fat-soluble vitamins and other fat-soluble nutrients is inhibited by the use of orlistat. [4]

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. [4] Orlistat can also impair absorption of the antiarrhythmic amiodarone. [29] The Medicines and Healthcare products Regulatory Agency (MHRA) has suggested the possibility that orlistat could reduce the absorption of antiretroviral HIV medications. [30]

Mechanism of action

Crystallographic structure of human fatty acid synthase thioesterase (rainbow color, N-terminus = blue, C-terminus = red) inhibited by orlistat (space-filling model; carbon = grey, oxygen = red, nitrogen = blue) 2PX6 orlistat.png
Crystallographic structure of human fatty acid synthase thioesterase (rainbow color, N-terminus = blue, C-terminus = red) inhibited by orlistat (space-filling model; carbon = grey, oxygen = red, nitrogen = blue)

Orlistat works by inhibiting gastric and pancreatic lipases, the enzymes that break down triglycerides in the intestine. [32] [33] When lipase activity is blocked, triglycerides from the diet are not hydrolyzed into absorbable free fatty acids, and instead are excreted unchanged. 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.

Orlistat was also found to inhibit the thioesterase domain of fatty acid synthase (FAS), an enzyme involved in the proliferation of cancer cells but not normal cells. However, potential side effects of orlistat, such as inhibition of other cellular off-targets or poor bioavailability, might hamper its application as an effective antitumor agent. One profiling study undertook a chemical proteomics approach to look for new cellular targets of orlistat, including its off-targets. [34] Orlistat also shows potential activity against the Trypanosoma brucei parasite. [35]

Orlistat prevents approximately 30% of dietary fat from being absorbed. [36]

Orlistat is available both with and without a prescription. [37] [4] [5] [38]

Australia and New Zealand

In Australia and New Zealand, orlistat is available as a "Pharmacist Only Medicine". [15] In 2007, the Committee 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". [39]

United States

Orlistat was initially approved by the U.S. Food and Drug Administration in April 1999 as a prescription-only medication. [40] On 23 January 2006, an FDA advisory panel voted 11 to 3 to recommend the approval of an OTC formulation of orlistat, to be sold under the brand name Alli by GlaxoSmithKline. [41] Approval was granted on 7 February 2007, [42] and Alli became the first weight loss drug officially sanctioned by the U.S. government for over-the-counter use. [43] Consumer advocacy organization Public Citizen opposed over-the-counter approval for orlistat. [14]

Alli became available in the U.S. in June 2007. It is sold as 60 mg capsules—half the dosage of prescription orlistat. [14] [43]

European Union and Switzerland

On 21 January 2009, the European Medicines Agency granted approval for the sale of orlistat without a prescription. [37] [44]

At least since September 2017, tablets with 60 mg orlistat can be freely sold in Swiss drugstores. Formulations with 120 mg per tablet require a prescription, but can be sold without one in pharmacies under an exemption rule, which is based on a list of easily diagnosable diseases. [45]

Generic formulations

U.S. patent protection for Xenical, originally to end on 18 June 2004, was extended by five years (until 2009) by the U.S. Patent and Trademark Office. The extension was granted on 20 July 2002, [46] and expired on 18 June 2009. [47]

Generic orlistat is available in Iran under the brand Venustat manufactured by Aburaihan Pharmaceutical co., in India, under the brands Orlean (Eris), Vyfat, Olistat, Obelit, Orlica and Reeshape. [48] In Russia, orlistat is available under the brand names Xenical (Hoffmann–La Roche), Orsoten/Orsoten Slim (KRKA d. d.) and Xenalten (OBL-Pharm). In Austria, orlistat is available under the brand name Slimox. In Malaysia, orlistat is available under the brand name Cuvarlix and is marketed by Pharmaniaga. In the Philippines orlistat is available under the brand name RedoXfat Plus manufactured by ATC Healthcare

Society and culture

Cost

At times, such as in spring 2012, orlistat has come into short supply, with consequent price increases because of nonavailability of one of the drug's components. [49]

Counterfeit products

In January 2010, the U.S. Food and Drug Administration issued an alert stating that some counterfeit versions of Alli sold over the Internet contain no orlistat, and instead contain the weight-loss drug sibutramine. The concentration of sibutramine in these counterfeit products is at least twice the amount recommended for weight loss. [50]

Related Research Articles

<span class="mw-page-title-main">Anti-obesity medication</span> Class of pharmacological agents

Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control excess body fat. These medications alter one of the fundamental processes of the human body, weight regulation, by: reducing appetite and consequently energy intake, increasing energy expenditure, redirecting nutrients from adipose to lean tissue, or interfering with the absorption of calories.

Steatorrhea is the presence of excess fat in feces. Stools may be bulky and difficult to flush, have a pale and oily appearance, and can be especially foul-smelling. An oily anal leakage or some level of fecal incontinence may occur. There is increased fat excretion, which can be measured by determining the fecal fat level.

<span class="mw-page-title-main">Dextropropoxyphene</span> Withdrawn opioid medication

Dextropropoxyphene is an analgesic in the opioid category, patented in 1955 and manufactured by Eli Lilly and Company. It is an optical isomer of levopropoxyphene. It is intended to treat mild pain and also has antitussive and local anaesthetic effects. The drug has been taken off the market in Europe and the US due to concerns of fatal overdoses and heart arrhythmias. It is still available in Australia, albeit with restrictions after an application by its manufacturer to review its proposed banning. Its onset of analgesia is said to be 20–30 minutes and peak effects are seen about 1.5–2.0 hours after oral administration.

<span class="mw-page-title-main">Rimonabant</span> Chemical compound

Rimonabant (also known as SR141716; trade names Acomplia, Zimulti) is an anorectic antiobesity drug approved in Europe in 2006 but was withdrawn worldwide in 2008 due to serious psychiatric side effects; it was never approved in the United States. Rimonabant is an inverse agonist for the cannabinoid receptor CB1 and was first-in-class for clinical development.

<span class="mw-page-title-main">Sibutramine</span> Appetite suppressant

Sibutramine, formerly sold under the brand name Meridia among others, is an appetite suppressant which has been discontinued in many countries. It works as a serotonin–norepinephrine reuptake inhibitor (SNRI) similar to certain antidepressants. Until 2010, it was widely marketed and prescribed as an adjunct in the treatment of obesity along with diet and exercise. It has been associated with increased cardiovascular diseases and strokes and has been withdrawn from the market in 2010 in several countries and regions including Australia, Canada, China, the European Union, Hong Kong, India, Mexico, New Zealand, the Philippines, Thailand, the United Kingdom, and the United States. However, the drug remains available in some countries.

<span class="mw-page-title-main">Pancreatic enzymes (medication)</span> Amylase, lipase, and protease mixture

Pancreatic enzymes, also known as pancreases or pancrelipase and pancreatin, are commercial mixtures of amylase, lipase, protease and lactase. They are used to treat malabsorption syndrome due to certain pancreatic problems. These pancreatic problems may be due to cystic fibrosis, surgical removal of the pancreas, long term pancreatitis, pancreatic cancer, or MODY 5, among others. The preparation is taken by mouth.

<span class="mw-page-title-main">Zonisamide</span> Chemical compound

Zonisamide, sold under the brand name Zonegran among others, is a medication used to treat the symptoms of epilepsy and Parkinson's disease. Chemically it is a sulfonamide. It serves as an anticonvulsant used primarily as an adjunctive therapy in adults with Parkinson's disease, partial-onset seizures; infantile spasm, mixed seizure types of Lennox–Gastaut syndrome, myoclonic and generalized tonic clonic seizure. Despite this it is also sometimes used as a monotherapy for partial-onset seizures.

<span class="mw-page-title-main">Exenatide</span> Medication

Exenatide, sold under the brand name Byetta among others, is a medication used to treat type 2 diabetes. It is used together with diet, exercise, and potentially other antidiabetic medication. It is a treatment option after metformin and sulfonylureas. It is given by injection under the skin.

<span class="mw-page-title-main">Dirlotapide</span> Chemical compound

Dirlotapide is a drug used to treat obesity in dogs. It is manufactured by Pfizer and Zoetis and marketed under the brand name Slentrol.

Cetilistat is a drug designed to treat obesity. It acts in the same way as the older drug orlistat (Xenical) 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.

<span class="mw-page-title-main">Lomitapide</span> Chemical compound

Lomitapide, sold under the brand name Juxtapid in the US and Lojuxta in the EU, is a medication used as a lipid-lowering agent for the treatment of familial hypercholesterolemia, developed by Aegerion Pharmaceuticals. It has been tested in clinical trials as single treatment and in combinations with atorvastatin, ezetimibe and fenofibrate.

<span class="mw-page-title-main">Naltrexone/bupropion</span> Medication for treatment of obesity

Naltrexone/bupropion, sold under the brand name Contrave among others, is a fixed-dose combination medication for the management of chronic obesity in adults in combination with a reduced-calorie diet and increased physical activity. It contains naltrexone, an opioid antagonist, and bupropion, an aminoketone atypical antidepressant. It is taken by mouth. Both medications have individually shown some evidence of effectiveness in weight loss, and the combination has been shown to have some synergistic effects on weight.

<span class="mw-page-title-main">Phentermine/topiramate</span> Obesity medication

Phentermine/topiramate, sold under the brand names Qsymia or QSIVA, is a combination drug of phentermine and topiramate used to treat obesity. It is used together with dietary changes and exercise. If less than 3% weight loss is seen after 3 months it is recommended the medication be stopped. The weight loss is modest. Effects on heart related health problems or death is unclear.

Management of obesity can include lifestyle changes, medications, or surgery. Although many studies have sought effective interventions, there is currently no evidence-based, well-defined, and efficient intervention to prevent obesity.

<span class="mw-page-title-main">Lipase inhibitors</span>

Lipase inhibitors are substances used to reduce the activity of lipases found in the intestine. Lipases are secreted by the pancreas when fat is present. The primary role of lipase inhibitors is to decrease the gastrointestinal absorption of fats. Fats then tend to be excreted in feces rather than being absorbed to be used as a source of caloric energy, and this can result in weight loss in individuals. These inhibitors could be used for the treatment of obesity, which can subsequently lead to Type 2 diabetes and cardiovascular diseases if not managed. An example of a lipase inhibitor is orlistat.

Metreleptin, sold under the brand name Myalept among others, is a synthetic analog of the hormone leptin used to treat various forms of dyslipidemia. It has been approved in Japan for metabolic disorders including lipodystrophy and in the United States as replacement therapy to treat the complications of leptin deficiency, in addition to diet, in patients with congenital generalized or acquired generalized lipodystrophy.

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Semaglutide is an antidiabetic medication used for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management. It is a peptide similar to the hormone glucagon-like peptide-1 (GLP-1), modified with a side chain. It can be administered by subcutaneous injection or taken orally. It is sold under the brand names Ozempic ( oh-ZEM-pick and Rybelsus for diabetes, and under the brand name Wegovy for weight loss.

<span class="mw-page-title-main">Discovery and development of gastrointestinal lipase inhibitors</span>

Lipase inhibitors belong to a drug class that is used as an antiobesity agent. Their mode of action is to inhibit gastric and pancreatic lipases, enzymes that play an important role in the digestion of dietary fat. Lipase inhibitors are classified in the ATC-classification system as A08AB . Numerous compounds have been either isolated from nature, semi-synthesized, or fully synthesized and then screened for their lipase inhibitory activity but the only lipase inhibitor on the market is orlistat . Lipase inhibitors have also shown anticancer activity, by inhibiting fatty acid synthase.

<span class="mw-page-title-main">Tirzepatide</span> Anti-diabetic and weight loss medication

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