Description
Orlistat was launched in the UK as Xenical for the long-term treatment
of obesity, preferably in conjunction with a moderately reduced calorie diet.
Orlistat is a tetrahydro-derivative of the natural hypolipaemic lipstatin (from
Streptomyces toxyfncini) and can be obtained either by hydrogenation of
lipstatine or by several different synthetic ways involving many steps from ( S ) -
rnalic acid. Orlistat is a potent inhibitor of gastrointestinal lipases required for the
lipolysis and digestion of dietary fat, in particular of pancreatic lipase ; as a
result, it prevents the absorption of about one third of the fat contained in food
and acts as an effective weight-reducing therapy. The outcomes of several
clinical trials involving thousands of obese patients showed that Orlistat
promotes a significant weight loss (often between 5 and 10% after one year) and
improves cardiovascular risk factors such as total cholesterol, LDL/HDL ratio,
blood glucose levels, insulin, blood pressure. Orlistat has minimal systemic
absorption, the majority of the compound itself being recovered in the feces ; it
does not affect other gastrointestinal processes, or the absorption of other
rnacronutrients such as carbohydrates and proteins.
Chemical Properties
Off-White Solid
Originator
Roche (Switzerland)
Uses
An antiobesity agent. A pancreatic lipase inhibitor. Antiobesity agent.
Uses
Orlistat is an antiobesity agent. Orlistat is an pancreatic lipase inhibitor.
Uses
Tetrahydrolipstatin (orlistat) is a semi-synthetic derivative of lipstatin, a metabolite isolated from Streptomyces toxytricini. Tetrahydrolipstatin acts as a potent, irreversible inhibitor of pancreatic lipase. In vivo, it blocks the absorption of triglycerides while allowing fatty acid absorption. Tetrahydrolipstatin is widely used for the treatment of obesity.
Definition
ChEBI: Orlistat is a carboxylic ester resulting from the formal condensation of the carboxy group of N-formyl-L-leucine with the hydroxy group of (3S,4S)-3-hexyl-4-[(2S)-2-hydroxytridecyl]oxetan-2-one. A pancreatic lipase inhibitor, it is used as an anti-obesity drug. It has a role as an EC 3.1.1.3 (triacylglycerol lipase) inhibitor, a bacterial metabolite, an EC 2.3.1.85 (fatty acid synthase) inhibitor and an anti-obesity agent. It is a beta-lactone, a L-leucine derivative, a member of formamides and a carboxylic ester.
Brand name
Xenical (Roche).
General Description
Pharmaceutical secondary standards for application in quality control, provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards.
Orlistat is a specific lipase inhibitor derived from lipostatin, which is naturally produced by Streptomyces toxytricini. Lipase inhibition induced by orlistat reduces the absorption of dietary fat, thereby contributing to caloric deficit.
Biological Activity
Hypolipemic pancreatic, gastric and carboxylester lipase inhibitor. Exhibits no activity at phospholipase A 2 , liver esterase, trypsin and chymotrypsin. Inhibits the thioesterase domain of fatty acid synthase, leading to cell cycle arrest at the G 1 /S boundary in vitro . Prevents the absorption of approximately one third of fat from food and exhibits progastrokinetic, antiobesity and antihypercholesterolemic activity in vivo .
Biochem/physiol Actions
Orlistat, used in obesity research, is a pancreatic lipase inhibitor that acts locally in the gastrointestinal tract to inhibit lipase.
Clinical Use
Adjunct in obesity
Metabolism
Orlistat is minimally absorbed and has no defined
systemic pharmacokinetics. The metabolism of orlistat
occurs mainly within the gastrointestinal wall to form 2
major inactive metabolites, M1 (4-member lactone ring
hydrolysed) and M3 (M1 with N-formyl leucine moiety
cleaved).
Faecal excretion of the unabsorbed drug is the major route
of elimination. Approximately 97% of the administered
dose is excreted in faeces and 83% of that as unchanged
orlistat.
References
1) Bisogno et al. (2006), Development of the first potent and specific inhibitors of endocannabinoid biosynthesis; Biochim. Biophys. Acta, 1761 205
2) Hadvary et al. (1991), The lipase inhibitor tetrahydrolipstatin bind covalently to the putative active site serine of pancreatic lipase; J. Biol. Chem., 266 2021
3) Kridel et al. (2004), Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity; Cancer Res., 64 2070
4) Ballinger and Peikin (2002), Orlistat: it’s current status as an anti-obesity drug; Eur. J. Pharmacol., 440 109
