Tetrahydrolipstatin

495.73500

495.73

95M8R751W8

DTXSID8023395

C29303

Crystals

A08AB01|A - Alimentary tract and metabolism

29322090

81.70000

10

Solid

0.976 g/cm3

39-41 °C

615.9ºC at 760 mmHg

326.3ºC

1.469

Practically insoluble in water

2-8ºC

9.77X10-14 mm Hg at 25 deg C (est)

Specific optical rotation at 20 °C: -32.0 deg ( c = 1 in chloroform)

Henry's Law constant = 1.13X10-9 atm-cu m/mole at 25 °C (est)

Orlistat has no pKa within the physiological range

241.2 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Hydroxyl radical reaction rate constant = 4.52x10-13 cu cm/molec-sec at 25 °C (est)

NONH for all modes of transport

3

OH3167600

P264, P270, P273, P301+P312, P330, P391, P501

H302

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription and over-the-counter drug products, incl orlistat, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|H411 (28.57%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]|P273, P391, and P501|Aggregated GHS information provided by 15 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The results of a massive overdose of Xenical are unknown, although the drug seems relatively harmless.

Orlistat acts my binding pancreatic and gastric lipase in the intestinal tract. Systemic absorption is not needed for its effect. Indeed, little of orally administered orlistat is absorbed (1% to 3%) and plasma levels are usually undetectable or less than 4 ng/mL (too little to inhibit serum lipase activities). Thus, systemic side effects of orlistat were not expected. In large clinical trials, serum liver test abnormalities were no more common with orlistat than with placebo therapy. Nevertheless, there have been several case reports of clinically apparent acute liver injury attributed to orlistat and in 2010 the FDA announced safety concerns regarding hepatotoxicity. The onset of injury in published cases was between 2 to 12 weeks of starting orlistat. The usual pattern of serum enzyme elevations was hepatocellular and some cases were severe with signs of hepatic failure and progression to death or need for liver transplantation. Features of hypersensitivity were not prominent and autoimmune markers were absent. None of the published cases included results of rechallenge. Thus, despite the number of published case reports, the hepatotoxicity of orlistat remains controversial and far from proven.

In a multiple-dose study in 30 normal-weight subjects, coadministration of orlistat and 40 grams of alcohol (eg, approximately 3 glasses of wine) did not result in alteration of alcohol pharmacokinetics, orlistat pharmacodynamics (fecal fat excretion), or systemic exposure to orlistat.|Preliminary data from a orlistat and cyclosporine drug interaction study indicate a reduction in cyclosporine plasma levels when orlistat was coadministered with cyclosporine.|A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption when concomitantly administered with orlistat. Orlistat inhibited absorption of a vitamin E acetate supplement by approximately 60%. The effect of orlistat on the absorption of supplemental vitamin D, vitamin A, and nutritionally-derived vitamin K is not known at this time.|In 12 normal-weight subjects receiving orlistat 80 mg three times a day for 5 days, orlistat did not alter the pharmacokinetics or pharmacodynamics (blood glucose-lowering) of glyburide.|For more Interactions (Complete) data for ORLISTAT (6 total), please visit the HSDB record page.

As with any weight-loss agent, the potential exists for misuse of orlistat in inappropriate patient populations (eg, patients with anorexia nervosa or bulimia).

>99% bound to plasma proteins (lipoproteins and albumin were major binding proteins).

While data specific to orlistat were not located(SRC, 2007), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

For obesity management including weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. Also used to reduce the risk for weight regain after prior weight loss. Use of orlistat is pending revision due to reports of liver-related adverse events.|FDA Label|Xenical is indicated in conjunction with a mildly hypocaloric diet for the treatment of obese patients with a body mass index (BMI) greater or equal to 30 kg/m2, or overweight patients (BMI > 28 kg/m2) with associated risk factors.Treatment with orlistat should be discontinued after 12 weeks if patients have been unable to lose at least 5% of the body weight as measured at the start of therapy.|Alli is indicated for weight loss in adults who are overweight (body mass index, BMI, ≥ 28 kg/m2) and should be taken in conjunction with a mildly hypocaloric, lower-fat diet.

Orlistat is an inhibitor of pancreatic and gastric lipase and a commonly used weight loss agent that is available both by prescription and over-the-counter. Orlistat has been linked to rare instances of acute liver injury, some of which have been severe.

Weight Loss Agents

Anti-Obesity Agents|The Food and Drug Administration (FDA) today-(February 07, 2007) approved orlistat capsules as an over-the-counter (OTC) weight loss aid for overweight adults. Orlistat was initially approved in 1999 as a prescription drug to treat obesity, and remains a prescription drug for obesity at a higher dose than the OTC version. OTC orlistat will be manufactured by GlaxoSmithKline under the name Alli and is indicated for use in adults ages 18 years and older along with a reduced-calorie, low-fat diet, and exercise program.|Orlistat is indicated for the management of obesity in persons with an initial body mass index (BMI) greater than or equal to 30 kg per square meter of body surface area (kg/sq m), or a BMI greater than or equal to 27 kg/sq m when other risk factors (such as hypertension, diabetes, or dyslipidemia are present. Orlistat should be use in conjunction with a reduced calorie diet for management of obesity, including weight loss, weight maintenance, and reduction of the risk of weight gain following previous weight loss. Weight loss has been observed within 2 week of initiation or orlistat therapy. /Included in US product label/

Chronic malabsorption syndrome or cholestasis /are contraindications for orlistat therapy/|/Orlistat is contraindicated in patients with/ known hypersensitivity to orlistat or any ingredient in the formulation.|Caution /is advised/ in patients with a history of hyperoxaluria or calcium oxalate nephrolithiasis.|/Clinician should/ rule out organic causes of obesity (e.g., hypothyroidism) /before initiating treatment/.|For more Drug Warnings (Complete) data for ORLISTAT (12 total), please visit the HSDB record page.

Orlistat is a lipase inhibitor for obesity management that acts by inhibiting the absorption of dietary fats. At the recommended therapeutic dose of 120 mg three times a day, orlistat inhibits dietary fat absorption by approximately 30%. It works by inhibiting pancreatic lipase, an enzyme that breaks down fat in the intestine. Without this enzyme, fat from the diet is excreted undigested and not absorbed by the body. Because some vitamins are fat soluble, the effect of orlistat is to reduce their body absorption. Therefore the drug should only be taken in conjuction with fatty meals, and a multivitamin tablet containing these vitamins (D E K and beta-carotene) should be taken once a day, at least 2 hours before or after taking the drug. In the March 15, 2004 issue of Cancer Research, [1] Steven J. Kridel et al. state that orlistat may also inhibit growth of prostate cancer, and in theory may be useful in treating other cancers, by interfering with the metabolism of fats.

Agents that increase energy expenditure and weight loss by neural and metabolic regulation. (See all compounds classified as Anti-Obesity Agents.)|Substances that alter the metabolism of LIPIDS. (See all compounds classified as Lipid Regulating Agents.)|Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)

Systemic absorption of orlistat is minimal, however systemic absorption of the drug is not needed for activity.|Following a single oral dose of 360 mg 14C-orlistat in both normal weight and obese subjects, fecal excretion of the unabsorbed drug was found to be the major route of elimination. Orlistat and its M1 and M3 metabolites were also subject to biliary excretion.|Orlistat works locally within the GI tract, and therefore systemic absorption of the drug is not required for activity. In fact, systemic absorption of orlistat is minimal, and effects on systemic lipases are unlikely. Fecal excretion of unabsorbed drug is the major route of elimination.|Systemic exposure to orlistat is minimal. Following oral dosing with 360 mg 14C-orlistat, plasma radioactivity peaked at approximately 8 hours; plasma concentrations of intact orlistat were near the limits of detection (<5 ng/mL). In therapeutic studies involving monitoring of plasma samples, detection of intact orlistat in plasma was sporadic and concentrations were low (<10 ng/mL or 0.02 uM), without evidence of accumulation, and consistent with minimal absorption.|The average absolute bioavailability of intact orlistat was assessed in studies with male rats at oral doses of 150 and 1000 mg/kg/day and in male dogs at oral doses of 100 and 1000 mg/kg/day and found to be 0.12%, 0.59% in rats and 0.7%, 1.9% in dogs, respectively.|In vitro orlistat was >99% bound to plasma proteins (lipoproteins and albumin were major binding proteins). Orlistat minimally partitioned into erythrocytes.|For more Absorption, Distribution and Excretion (Complete) data for ORLISTAT (6 total), please visit the HSDB record page.

Metabolized primarily within the gastrointestinal wall forming relatively inactive metabolites. Metabolites M1 (4-member lactone ring hydrolyzed) and M3 (M1 with N-formyl leucine moiety cleaved) accounted for approximately 42% of total radioactivity in plasma. M1 and M3 have an open beta-lactone ring and extremely weak lipase inhibitory activity (1000- and 2500-fold less than orlistat, respectively).|Based on animal data, it is likely that the metabolism of orlistat occurs mainly within the gastrointestinal wall. Based on an oral 14C-orlistat mass balance study in obese patients, two metabolites, M1 (4-member lactone ring hydrolyzed) and M3 (M1 with N-formyl leucine moiety cleaved), accounted for approximately 42% of total radioactivity in plasma. M1 and M3 have an open beta-lactone ring and extremely weak lipase inhibitory activity (1000- and 2500-fold less than orlistat, respectively). In view of this low inhibitory activity and the low plasma levels at the therapeutic dose (average of 26 ng/mL and 108 ng/mL for M1 and M3, respectively, 2 to 4 hours after a dose), these metabolites are considered pharmacologically inconsequential. The primary metabolite M1 had a short half-life (approximately 3 hours) whereas the secondary metabolite M3 disappeared at a slower rate (half-life approximately 13.5 hours). In obese patients, steady-state plasma levels of M1, but not M3, increased in proportion to orlistat doses.

1 to 2 hours.|Based on limited data, the half-life of the absorbed orlistat is in the range of 1 to 2 hours.|Based on an oral 14C-orlistat mass balance study in obese patients, ... the primary metabolite M1 had a short half-life (approximately 3 hours) whereas the secondary metabolite M3 disappeared at a slower rate (half-life approximately 13.5 hours). In obese patients, steady-state plasma levels of M1, but not M3, increased in proportion to orlistat doses.

Orlistat is a reversible inhibitor of lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine residue site of gastric and pancreatic lipases. The inactivated enzymes are thus unavailable to hydrolyze dietary fat in the form of triglycerides into absorbable free fatty acids and monoglycerides. As undigested triglycerides are not absorbed, the resulting caloric deficit may have a positive effect on weight control.|Orlistat is a reversible inhibitor of lipases. It exerts its therapeutic activity in the lumen of the stomach and small intestine by forming a covalent bond with the active serine residue site of gastric and pancreatic lipases. The inactivated enzymes are thus unavailable to hydrolyze dietary fat in the form of triglycerides into absorbable free fatty acids and monoglycerides. As undigested triglycerides are not absorbed, the resulting caloric deficit may have a positive effect on weight control. Systemic absorption of the drug is therefore not needed for activity. At the recommended therapeutic dose ... orlistat inhibits dietary fat absorption by approximately 30%.|Orlistat, a reversible inhibitor of gastric and pancreatic lipases, exhibits antiobesity and antilipemic activity. The drug also inhibits certain other (e.g., microbial, carboxylester [for hydrolysis of vitamin esters]) lipases. Orlistat is a synthetic derivative of naturally occurring lipstatin.|Unlike most other currently available antiobesity agents, orlistat does not exert anorexigenic (appetite suppressant) effects. Instead, orlistat exerts its antiobesity effect by decreasing the absorption of dietary fats (triacylglycerols) in the intestinal lumen via inhibition of triglyceride hydrolysis; at recommended dosages, approximately one-third of dietary fat will not be absorbed. By preventing triglyceride hydrolysis, the drug decreases intestinal concentrations of absorbable free fatty acids and monoglycerides.|Orlistat, an antiobesity drug, is cytostatic and cytotoxic to tumor cells. The antitumor activity of orlistat can be attributed to its ability to inhibit the thioesterase domain of fatty acid synthase (FAS). The objective of the present study was to test the effect of orlistat on endothelial cell proliferation and angiogenesis. Orlistat inhibits endothelial cell FAS, blocks the synthesis of fatty acids, and prevents endothelial cell proliferation. More significantly, orlistat inhibits human neovascularization in an ex vivo assay, which suggests that it may be useful as an antiangiogenic drug. The mechanism of these effects can be traced to the fact that orlistat prevents the display of the vascular endothelial growth factor (VEGF) receptor (VEGFR2/KDR/Flk1) on the endothelial cell surface. Thus, orlistat is an antiangiogenic agent with a novel mechanism of action.

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/HUMAN EXPOSURE STUDIES/ Single doses of 800 mg orlistat and multiple doses of up to 400 mg three times a day for 15 days have been studied in normal weight and obese subjects without significant adverse findings. ... Based on human and animal studies, systemic effects attributable to the lipase-inhibiting properties of orlistat should be rapidly reversible.|/HUMAN EXPOSURE STUDIES/ The aim of the present study was to assess whether oral administration of orlistat inhibits cholecystokinin (CCK) release in response to a test meal and thus causes impaired gallbladder emptying. 22 healthy volunteers were given a test meal consisting of 200 mL dairy cream and two teaspoons of chocolate powder (552 kcal=2328 kJ; 56.0 g fat; 5.2 g proteins, 6.6 g carbohydrates), with and without oral application of 120 mg orlistat. Gallbladder volume was determined by ultrasound before and 5, 10, 20, 30 and 40 min after meal ingestion. In parallel, a venous blood sample was collected for the measurement of bioactive CCK. CCK activity was assessed using a bioassay with isolated rat pancreatic acini cells. Oral administration of orlistat significantly impairs gallbladder emptying. After ingestion of the test meal the gallbladder contracted by 78.5% in the control group, whereas the test group with orlistat only showed a contraction of 45.7% (p<0.01). Maximal contraction was reached after 35 to 40 min, the maximal gallbladder emptying was delayed up to 10 min by orlistat. Orlistat induced a significant reduction of bioactive CCK levels in response to a test meal (CCK(max) with orlistat=4.1 pmol/L; CCK(max) without orlistat=7.8 pmol/L). CCK levels were reduced by 47% and the onset of maximal CCK secretion was delayed up to 10 min. The inhibition of intestinal lipolytic activity by orlistat results in reduced gallbladder emptying through inhibition of meal-mediated CCK release.|/CASE REPORTS/ An 18-year-old Caucasian woman with type 1 diabetes for the past 3 years who had a progressive increase in weight, reaching 89 kg, and a height of 164 cm (BMI 33 kg/sq m). She was administered several weight-reducing regimens, but to no avail. One month before her hospitalization, she began taking, on her own, orlistat (120 mg three times per day) in addition to a low-calorie diet. This was accompanied by one to three watery bowel movements per day. She was progressively lethargic, and her insulin dose requirement increased from 86 to 98 U/day, in three preprandial injections of regular insulin with one evening dose of long-acting insulin. She had no other underlying illnesses and was not on any other medication. Her home blood glucose monitoring revealed progressive worsening of her diabetes control. On the day of presentation in the emergency room, she was complaining of severe lethargy, abdominal discomfort, nausea, and two episodes of vomiting. Laboratory data showed severe hyperglycemia (blood glucose 550 mg/dl), acidosis (pH 7.0), hyperosmolar state (Na 153 mEq/L, K 3.0 mEq/L, BUN 60 mg/dL, creatinine 1.8 mg/dL), severe ketosis (ketone bodies 40 mg/dL), and positive urinary ketones. She was afebrile (37.2 °C), weighed 85 kg, had an HbA1c 12%, and was dehydrated (10% of her body weight). Orlistat was stopped, and the patient was started on intravenous hydration and insulin. The patient showed significant improvement over a period of 5 days. On discharge, she was back on her baseline insulin dosage of 82 U/day, and she was hemodynamically stable. In this patient, orlistat, probably secondary to the watery stools, seemed to have progressively caused dehydration and a decrease in intravascular volume. Initially, this lead to insulin resistance and increased insulin requirements, followed by DKA.|/CASE REPORTS/ A 42-year-old white woman developed symptoms of constipation, polyuria, polydipsia, and increased lower-leg edema after 2 weeks of treatment with orlistat 120 mg 3 times daily. The drug was discontinued for 4 days and the symptoms resolved. On reinstitution of the orlistat treatment, the symptoms reappeared within 2 days. Thereafter, the medication was permanently discontinued. Common gastrointestinal adverse reactions associated with orlistat use include fecal urgency and abdominal pain and discomfort. Pedal edema has also been reported to occur, although less frequently. No reports were discovered documenting the occurrence of constipation, polydipsia, and polyuria associated with the use of orlistat. Despite careful consideration of other possible causes of these symptoms, the temporal association between initiation, discontinuation, and rechallenge of orlistat and the patient's symptoms suggest a medication-related adverse event. Based on the Naranjo probability scale, the likelihood that orlistat was the cause of this cluster of adverse effects is possible.|For more Human Toxicity Excerpts (Complete) data for ORLISTAT (11 total), please visit the HSDB record page.

1-((3-hexyl-4-oxo-2-oxetanyl)methyl)dodecyl-2-formamido-4-methylvalerate

/Oral formulations/: Capsules 120 mg Xenical with povidone, (Roche).|Trade name: Xenical|Trade names: Alli.

Analyte: orlistat; matrix: blood (plasma); procedure: high-performance liquid chromatography coupled with ion-spray tandem mass spectrometric detection; limit of detection: 0.1 ng/mL|Analyte: orlistat; matrix: blood (plasma); procedure: high-performance liquid chromatography with tandem mass spectrometric detection; limit of quantitation: 0.3 ng/mL

Human drugs -> Xenical -> EMA Drug Category|Antiobesity preparations, excl. diet products -> Human pharmacotherapeutic group|Human drugs -> Alli (previously Orlistat GSK) -> EMA Drug Category|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients