Orlistat

Orlistat

Systematic (IUPAC) name
(S)-((S)-1-((2S,3S)-3-Hexyl-4-oxooxetan-2-yl)tridecan-2-yl) 2-formamido-4-methylpentanoate
Clinical data
Trade names	Xenical, alli
AHFS/Drugs.com	monograph
MedlinePlus	a601244
Licence data	EMA:Link, US FDA:link
Pregnancy category	AU: B1 US: X (Contraindicated)
Legal status	AU: S3 (Pharmacist only) UK: Pharmacy medicines US: OTC
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	Negligible
Protein binding	>99%
Metabolism	In the GI tract
Biological half-life	1 to 2 hours
Excretion	Fecal
Identifiers
CAS Number	96829-58-2 Y
ATC code	A08AB01 (WHO)
PubChem	CID: 3034010
IUPHAR/BPS	5277
DrugBank	DB01083 N
ChemSpider	2298564 Y
UNII	95M8R751W8 N
KEGG	D04028 Y
ChEMBL	CHEMBL175247 Y
Chemical data
Formula	C29H53NO5
Molecular mass	495.735 g/mol
SMILES O=C(O[C@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)CCCCCCCCCCC)[C@@H](NC=O)CC(C)C
InChI 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 Y Key:AHLBNYSZXLDEJQ-FWEHEUNISA-N Y
NY (what is this?)  (verify)

Orlistat (also known as tetrahydrolipstatin) is a drug designed to treat obesity. It is marketed as a prescription drug under the trade name Xenical by Roche in most countries, and is sold over-the-counter as Alli by GlaxoSmithKline in the United Kingdom and the United States. 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.

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

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 (4.4–6.6 lb) more than those not taking the drug over the course of a year. Orlistat also modestly reduces blood pressure and appears to prevent the onset of type 2 diabetes, whether from the weight loss itself or to other effects. In a large randomized controlled trial, orlistat was found to reduce the incidence of diabetes by nearly 40% in obese people.

Orlistat is notorious 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. In the United States and the European Union, orlistat is available for sale without a prescription. Over-the-counter approval was controversial in the United States, with consumer advocacy group Public Citizen repeatedly opposing it on safety and efficacy grounds. Generic formulations of orlistat are available in some countries. In Australia it is listed as an S3 medication and so is available over the counter in pharmacies.

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.

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. After orlistat was stopped, a significant number of subjects regained weight—up to 35% of the weight they had lost.

The incidence of type 2 diabetes in an obese population over four years is decreased with orlistat (6.2%) compared to placebo (9.0%). Long-term use of orlistat also leads to a modest reduction in blood pressure (mean reductions of 2.5 and 1.9 mmHg in systolic and diastolic blood pressure respectively).

Contraindications

Orlistat is contraindicated in:

• Malabsorption
• Hypersensitivity to orlistat
• Reduced gallbladder function (e.g. after cholecystectomy)
• Pregnancy and breastfeeding
• Use caution with: obstructed bile duct, impaired liver function, and pancreatic disease

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. GlaxoSmithKline recommends that all users be cautious of the possible side effects until they "have a sense of any treatment effects". 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. The manual for Alli makes it clear that orlistat treatment involves aversion therapy, encouraging the user to associate eating fat with unpleasant treatment effects.

According to Roche, side effects are most severe when beginning therapy and may decrease in frequency with time; this is supported by the results of the XENDOS study, which found that 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. 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.

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.

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. The putative mechanism for this effect is postulated to be excessive oxalate absorption from the gut and its subsequent deposition in the kidney, with excessive oxalate absorption being a known consequence of fat malabsorption.

An April 2013 study published in the British Medical Journal looked at 94,695 patients receiving orlistat in the UK between 1999 and 2011. This study showed no evidence of an increased risk of liver injury during treatment. They concluded:

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—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. 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.

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. ACF lesions are believed to be one of the earliest precursors of colon cancer.

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.

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. Orlistat can also impair absorption of the antiarrhythmic amiodarone. The MHRA has recently suggested that Orlistat could theoretically reduce the absorption of antiretroviral HIV medications.

Mechanism of action

Crystallographic structure of human fatty acid synthase (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. 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 recently 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. Orlistat also show potential activities mycobacteria and Trypanosoma brucei parasite (See further reading).

At the standard prescription dose of 120 mg three times daily before meals, orlistat prevents approximately 30% of dietary fat from being absorbed, and about 25% at the standard over-the-counter dose of 60 mg. Higher doses do not produce more potent effects.

Legal status

Packaging of orlistat (Xenical) 120 mg capsules, as sold in Canada

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

In 2009, Roche began recruiting in Russia for a clinical trial of Xenical in obese teenagers between the ages of 12 and 14.

Australia and 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 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". Xenical has recently began being advertised direct-to-customers again.

United States

On 23 January 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 /ˈælaɪ/ by GlaxoSmithKline. Approval was granted on 7 February 2007, and alli became the first weight loss drug officially sanctioned by the U.S. government for over-the-counter use. Consumer advocacy organization Public Citizen opposed over-the-counter approval for orlistat.

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

European Union

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

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, and expired on 18 June 2009.

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. In Russia, orlistat is available under the brand names Xenical (Hoffmann–La Roche), Orsoten/Orsoten Slim (KRKA d. d.) and Xenalten (OBL-Pharm). In Malaysia, orlistat is available under the brand name Cuvarlix and is marketed by Pharmaniaga.

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.

Synthesis

Bio

Isoln from fermentation broth of Streptomyces toxytricini:

Chemical

Orlistat synthesis: see also:

Construction begins with the cyclohexanone acetal of L-malic acid. The carboxylic acid is first reduced by means of diborane, and then that is protected as its tert-Butyldiphenylsilyl (TBDPS) ether. The acetal ring is then opened by means of NaOMe in MeOH. The resulting ester is then reduced, and the resulting hydroxyl is converted to a leaving group by reaction with naphthylsulfonyl chloride. Treatment with a strong base leads to internal displacement and thus formation of the oxirane. The ring is then opened with the lithium reagent from the exchange of n-bromodecane with BuLi to afford the long chain product.

Addition of the second part of the molecule starts by first protecting the free hydroxyl group as its benzyl ether by exchange with O-benzyliminotrifluoroacetamide. The silyl protecting group on the other hydroxyl is then removed by means of HF. Swern oxidation then converts that the an aldehyde group. TiCl4 catalyzed carbocation addition to a carbonyl group then serves to couple the two halves of the molecule. Addition of the ambidentate allylic carbocation from silyl intermediate in the presence of titanocene dichloride proceeds via the more substituted terminus of that cation to give the condensation product. Stereoselectivity is assured by asymmetric from the adjacent alcohol; that function traces its chirality back to malic acid.

Ozonization of the terminal olefin followed an oxidative workup gives the carboxylic acid (9). Treatment of this with benzenesulfonyl chloride in pyridine results in the formation of the butyrolactone ring to give intermediate 10; the hexyl group on that ring, however, occupies the reverse configuration from that in the natural product. Reaction of the product with LDA enolizes that position with consequent epimerization to the desired stereochemistry; hydrogenolysis of the benzyl group then affords the intermediate 11; note that this oxygen also occupies the reverse configuration.

A version of the Mitsunobu reaction is used both to add the last fragment and to invert that oxygen. Reaction with N-formylleucine under Mitsunobu conditions affords orlistat.

External links

• Official US Alli site from GlaxoSmithKline
• Official UK Alli site from GlaxoSmithKline
• Official Xenical site from Roche
• Official Philippines (Asia) Xenical site from Roche
• FDA Consumer Info at the Wayback Machine (archived January 26, 2008)