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Chemical Compound Review

orlistat     [(2S)-1-[(2S,3S)-3-hexyl-4- oxo-oxetan-2...

Synonyms: Xenical, Orlipastat, Alli, Orlipastatum, THLP, ...
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Disease relevance of Tetrahydrolipstatin


Psychiatry related information on Tetrahydrolipstatin

  • After 4 years' treatment, the cumulative incidence of diabetes was 9.0% with placebo and 6.2% with orlistat, corresponding to a risk reduction of 37.3% (P = 0.0032) [6].
  • All subjects had an 8-wk run-in period of dietary modification and then randomized to receive either metformin (500 mg three times daily) or orlistat (120 mg three times daily) for 3 months [7].
  • Evidence on longer-term benefits of orlistat (>2 years) will be of importance for future decision-making [8].
  • The overall Eating Disorder Inventory 2 score at week 24 was significantly lower in patients treated with orlistat than in those in the placebo group (p = 0.011) [9].
  • Weight reduction by means of life-style changes, supported by medical interventions with inhibitors of intestinal fat absorption (e.g. Orlistat) or appetite suppressants (e.g. Sibutramine), is essential in order to decrease the risk of atherosclerosis [10].

High impact information on Tetrahydrolipstatin

  • CONCLUSIONS: Two-year treatment with orlistat plus diet significantly promotes weight loss, lessens weight regain, and improves some obesity-related disease risk factors [1].
  • Density gradient analysis revealed that most of the secreted heart lipoproteins were LDLs, even when the labeling experiments were performed in the presence of tetrahydrolipstatin, an inhibitor of lipoprotein lipase [11].
  • During distentions, intragastric volumes were greater during infusion of LCT and MCT than during the respective THL conditions or SPE, but plasma CCK levels did not change [12].
  • Increasing doses of tetrahydrolipstatin induced a dose-dependent inhibition of duodenal lipase activity (P < 0.01); 120 mg tetrahydrolipstatin eliminated the postprandial lipase peak activity, free fatty acid levels decreased to < 5% of total fatty acids, and plasma cholecystokinin levels were suppressed by 77% (P < 0.01) [13].
  • METHODS: Fat hydrolysis was inhibited by intraduodenal perfusion of tetrahydrolipstatin, an irreversible lipase inhibitor [13].

Chemical compound and disease context of Tetrahydrolipstatin


Biological context of Tetrahydrolipstatin


Anatomical context of Tetrahydrolipstatin

  • Role of lipase in the regulation of postprandial gastric acid secretion and emptying of fat in humans: a study with orlistat, a highly specific lipase inhibitor [21].
  • A decrease in fat absorption by orlistat appears to favorably influence the ratio between intraabdominal and subcutaneous fat, which suggests that exogenous fat or its composition influences fat distribution [22].
  • Effects of equal weight loss with orlistat and placebo on body fat and serum fatty acid composition and insulin resistance in obese women [22].
  • The mean maximum percentage of ingested fat excreted in the feces was approximately 32% during orlistat administration compared with 5% during placebo administration [23].
  • Inhibition of LPL activity with tetrahydrolipstatin, a lipase active-site inhibitor, did not affect the LPL-mediated monocyte binding [24].

Associations of Tetrahydrolipstatin with other chemical compounds

  • Irrespective of dietary fat content, 3 weeks of combined treatment (Orl + CaP) decreased plasma UCB by approximately 50% (P < .01) and was more effective than phototherapy (P < .05) at the intensity provided [3].
  • The lipase inhibitor tetrahydrolipstatin binds covalently to the putative active site serine of pancreatic lipase [25].
  • LpL-mediated LDL selective uptake was not affected by the LpL inhibitor tetrahydrolipstatin but was nearly abolished by heparin, monoclonal anti-LpL antibodies, or chlorate treatment of cells and was not found using proteoglycan-deficient Chinese hamster ovary cells [26].
  • In the first 60 min after the meal blood glucose (p=0.001) and plasma insulin (p=0.01) concentrations were higher in patients who had taken orlistat; between 60 and 180 min plasma GLP-1 (p=0.02) concentrations were lower after orlistat than without orlistat [27].
  • The objective of this study was to evaluate and compare the effect of treatment with orlistat vs. metformin on the hormonal and biochemical features of patients with polycystic ovarian syndrome (PCOS) [7].
  • Plasma levels of CCK (by approximately 53%), PYY (by approximately 40%), and GLP-1 (by approximately 20%) were significantly lowered by Orlistat (P < 0.001), whereas ghrelin levels were unaffected by Orlistat treatment (P = 0.18) [28].

Gene context of Tetrahydrolipstatin

  • Inhibition of the enzymic activity with tetrahydrolipstatin (THL) significantly enhanced the effect of EDL, as reflected by a 5.2-fold increase in binding, a 2.6-fold increase in particle uptake and a 1.1-fold increase in CE selective uptake compared with incubations without THL [29].
  • Inhibition of extracellular TG hydrolysis with tetrahydrolipstatin (Orlistat) resulted in the absence of intracellular TG and FFA accumulation and was accompanied by the amelioration of ERK1/2 phosphorylation and MIP-1alpha gene expression [30].
  • This increase in selective CE uptake was observed in the presence of tetrahydrolipstatin, an inhibitor of the catalytically active site of HL, suggesting that this HL effect is independent from lipolysis [31].
  • LPL-dependent selective alphaTocH uptake was unaffected by the lipase inhibitor tetrahydrolipstatin but was substantially inhibited in cells where proteoglycan sulfation was inhibited by treatment with NaClO(3) [32].
  • Orlistat augments postprandial increases in glucagon-like peptide 1 in obese type 2 diabetic patients [33].

Analytical, diagnostic and therapeutic context of Tetrahydrolipstatin

  • METHODS: In a double-blind study, 15 healthy subjects were studied on 5 occasions during which LCT or MCT emulsions (2 kcal/min), with or without 120 mg tetrahydrolipstatin (THL, lipase inhibitor), or sucrose polyester (SPE, nondigestible fat) were infused intraduodenally in randomized order [12].
  • Orl treatment for 2 weeks (HF diet) reduced plasma UCB concentrations similar to phototherapy (-34% and -28%, respectively); the combination of both was more effective than either treatment alone (-48%; P < .001) [3].
  • METHODS: Obese patients with diabetes (n = 33) and obese nondiabetic patients (n = 27) were given orlistat, 120 mg 3 times daily, without a concomitant hypocaloric diet for 6 months (body mass index [calculated as weight in kilograms divided by the square of height in meter; kg/m2] range, 27.8-47.4) [34].
  • In a two way cross over study with two test periods of five days, separated by at least 14 days, orlistat 120 mg three times daily or placebo was given with standardised daily meals [21].
  • They did this on two separate occasions, with and without 120 mg orlistat, and while in the seated position with their back against a gamma camera [27].


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  2. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Kridel, S.J., Axelrod, F., Rozenkrantz, N., Smith, J.W. Cancer Res. (2004) [Pubmed]
  3. Effective oral treatment of unconjugated hyperbilirubinemia in Gunn rats. Hafkamp, A.M., Havinga, R., Sinaasappel, M., Verkade, H.J. Hepatology (2005) [Pubmed]
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  5. Orlistat-induced cutaneous leukocytoclastic vasculitis. Gonzalez-Gay, M.A., Garcia-Porrua, C., Lueiro, M., Fernandez, M.L. Arthritis Rheum. (2002) [Pubmed]
  6. 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. Torgerson, J.S., Hauptman, J., Boldrin, M.N., Sjöström, L. Diabetes Care (2004) [Pubmed]
  7. Orlistat is as beneficial as metformin in the treatment of polycystic ovarian syndrome. Jayagopal, V., Kilpatrick, E.S., Holding, S., Jennings, P.E., Atkin, S.L. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  8. A health economic model to assess the long-term effects and cost-effectiveness of orlistat in obese type 2 diabetic patients. Lamotte, M., Annemans, L., Lefever, A., Nechelput, M., Masure, J. Diabetes Care (2002) [Pubmed]
  9. Effect of orlistat in obese patients with binge eating disorder. Golay, A., Laurent-Jaccard, A., Habicht, F., Gachoud, J.P., Chabloz, M., Kammer, A., Schutz, Y. Obes. Res. (2005) [Pubmed]
  10. Obesity and free fatty acids: double trouble. Castro Cabezas, M., Halkes, C.J., Erkelens, D.W. Nutrition, metabolism, and cardiovascular diseases : NMCD. (2001) [Pubmed]
  11. Apo B100-containing lipoproteins are secreted by the heart. Borén, J., Véniant, M.M., Young, S.G. J. Clin. Invest. (1998) [Pubmed]
  12. Fat digestion modulates gastrointestinal sensations induced by gastric distention and duodenal lipid in humans. Feinle, C., Rades, T., Otto, B., Fried, M. Gastroenterology (2001) [Pubmed]
  13. Hydrolysis of dietary fat by pancreatic lipase stimulates cholecystokinin release. Hildebrand, P., Petrig, C., Burckhardt, B., Ketterer, S., Lengsfeld, H., Fleury, A., Hadváry, P., Beglinger, C. Gastroenterology (1998) [Pubmed]
  14. Long-term pharmacotherapy of obesity 2000: a review of efficacy and safety. Glazer, G. Arch. Intern. Med. (2001) [Pubmed]
  15. Identification and structural characterization of an unusual mycobacterial monomeromycolyl-diacylglycerol. Kremer, L., de Chastellier, C., Dobson, G., Gibson, K.J., Bifani, P., Balor, S., Gorvel, J.P., Locht, C., Minnikin, D.E., Besra, G.S. Mol. Microbiol. (2005) [Pubmed]
  16. Long-term pharmacotherapy for obesity. Klein, S. Obes. Res. (2004) [Pubmed]
  17. Comparative evaluation of fecal fat excretion induced by orlistat and chitosan. Guerciolini, R., Radu-Radulescu, L., Boldrin, M., Dallas, J., Moore, R. Obes. Res. (2001) [Pubmed]
  18. {beta}-Cell Lipases and Insulin Secretion. Fex, M., Lucas, S., Winzell, M.S., Ahr??n, B., Holm, C., Mulder, H. Diabetes (2006) [Pubmed]
  19. Structure and activity of rat pancreatic lipase-related protein 2. Roussel, A., Yang, Y., Ferrato, F., Verger, R., Cambillau, C., Lowe, M. J. Biol. Chem. (1998) [Pubmed]
  20. Differential effects of lipoprotein lipase on tumor necrosis factor-alpha and interferon-gamma-mediated gene expression in human endothelial cells. Kota, R.S., Ramana, C.V., Tenorio, F.A., Enelow, R.I., Rutledge, J.C. J. Biol. Chem. (2005) [Pubmed]
  21. Role of lipase in the regulation of postprandial gastric acid secretion and emptying of fat in humans: a study with orlistat, a highly specific lipase inhibitor. Borovicka, J., Schwizer, W., Guttmann, G., Hartmann, D., Kosinski, M., Wastiel, C., Bischof-Delaloye, A., Fried, M. Gut (2000) [Pubmed]
  22. Effects of equal weight loss with orlistat and placebo on body fat and serum fatty acid composition and insulin resistance in obese women. Tiikkainen, M., Bergholm, R., Rissanen, A., Aro, A., Salminen, I., Tamminen, M., Teramo, K., Yki-Järvinen, H. Am. J. Clin. Nutr. (2004) [Pubmed]
  23. Retrospective population-based analysis of the dose-response (fecal fat excretion) relationship of orlistat in normal and obese volunteers. Zhi, J., Melia, A.T., Guerciolini, R., Chung, J., Kinberg, J., Hauptman, J.B., Patel, I.H. Clin. Pharmacol. Ther. (1994) [Pubmed]
  24. Lipoprotein lipase can function as a monocyte adhesion protein. Obunike, J.C., Paka, S., Pillarisetti, S., Goldberg, I.J. Arterioscler. Thromb. Vasc. Biol. (1997) [Pubmed]
  25. The lipase inhibitor tetrahydrolipstatin binds covalently to the putative active site serine of pancreatic lipase. Hadváry, P., Sidler, W., Meister, W., Vetter, W., Wolfer, H. J. Biol. Chem. (1991) [Pubmed]
  26. Lipoprotein lipase-mediated selective uptake from low density lipoprotein requires cell surface proteoglycans and is independent of scavenger receptor class B type 1. Seo, T., Al-Haideri, M., Treskova, E., Worgall, T.S., Kako, Y., Goldberg, I.J., Deckelbaum, R.J. J. Biol. Chem. (2000) [Pubmed]
  27. Effects of lipase inhibition on gastric emptying of, and on the glycaemic, insulin and cardiovascular responses to, a high-fat/carbohydrate meal in type 2 diabetes. O'Donovan, D., Horowitz, M., Russo, A., Feinle-Bisset, C., Murolo, N., Gentilcore, D., Wishart, J.M., Morris, H.A., Jones, K.L. Diabetologia (2004) [Pubmed]
  28. Orlistat inhibition of intestinal lipase acutely increases appetite and attenuates postprandial glucagon-like peptide-1-(7-36)-amide-1, cholecystokinin, and peptide YY concentrations. Ellrichmann, M., Kapelle, M., Ritter, P.R., Holst, J.J., Herzig, K.H., Schmidt, W.E., Schmitz, F., Meier, J.J. J. Clin. Endocrinol. Metab. (2008) [Pubmed]
  29. Endothelial cell-derived lipase mediates uptake and binding of high-density lipoprotein (HDL) particles and the selective uptake of HDL-associated cholesterol esters independent of its enzymic activity. Strauss, J.G., Zimmermann, R., Hrzenjak, A., Zhou, Y., Kratky, D., Levak-Frank, S., Kostner, G.M., Zechner, R., Frank, S. Biochem. J. (2002) [Pubmed]
  30. The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritoneal macrophages. Saraswathi, V., Hasty, A.H. J. Lipid Res. (2006) [Pubmed]
  31. Hepatic lipase mediates an increase in selective uptake of high-density lipoprotein-associated cholesteryl esters by human Hep 3B hepatoma cells in culture. Rinninger, F., Mann, W.A., Kaiser, T., Ahle, S., Meyer, N., Greten, H. Atherosclerosis (1998) [Pubmed]
  32. Effects of lipoprotein lipase on uptake and transcytosis of low density lipoprotein (LDL) and LDL-associated alpha-tocopherol in a porcine in vitro blood-brain barrier model. Goti, D., Balazs, Z., Panzenboeck, U., Hrzenjak, A., Reicher, H., Wagner, E., Zechner, R., Malle, E., Sattler, W. J. Biol. Chem. (2002) [Pubmed]
  33. Orlistat augments postprandial increases in glucagon-like peptide 1 in obese type 2 diabetic patients. Damci, T., Yalin, S., Balci, H., Osar, Z., Korugan, U., Ozyazar, M., Ilkova, H. Diabetes Care (2004) [Pubmed]
  34. The effect of orlistat-induced weight loss, without concomitant hypocaloric diet, on cardiovascular risk factors and insulin sensitivity in young obese Chinese subjects with or without type 2 diabetes. Tong, P.C., Lee, Z.S., Sea, M.M., Chow, C.C., Ko, G.T., Chan, W.B., So, W.Y., Ma, R.C., Ozaki, R., Woo, J., Cockram, C.S., Chan, J.C. Arch. Intern. Med. (2002) [Pubmed]
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