Orlistat

15

Orlistat has no pKa within the physiological range

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.

/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.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Orlistat

vMost-DILI-concern

8

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ ... The present study was designed to verify the effects of Orlistat on the formation of rat colonic aberrant crypt foci (ACF) and cell proliferation evaluated by the PCNA method. Male Wistar rats received either a standard diet or a high fat diet (HFD), supplemented or not with Orlistat (200 mg/kg chow) and two doses of the carcinogen dimethyl-hydrazine (25 mg/Kg). After 30 days, Orlistat was associated to a significant increase in the number of colonic ACFs and cell proliferation in DMH-treated animals, independently of the HFD.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Carcinogenicity studies in rats and mice did not show a carcinogenic potential for orlistat at doses up to 1000 mg/kg/day and 1500 mg/kg/day, respectively. For mice and rats, these doses are 38 and 46 times the daily human dose calculated on an area under concentration vs time curve basis of total drug-related material.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ When given to rats at a dose of 400 mg/kg/day in a fertility and reproduction study, orlistat had no observable adverse effects. This dose is 12 times the daily human dose calculated on a body surface area (mg/sq m) basis.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Teratogenicity studies were conducted in rats and rabbits at doses up to 800 mg/kg/day. Neither study showed embryotoxicity or teratogenicity. This dose is 23 and 47 times the daily human dose calculated on a body surface area (mg/sq m) basis for rats and rabbits, respectively. The incidence of dilated cerebral ventricles was increased in the mid- and high-dose groups of the rat teratology study. These doses were 6 and 23 times the daily human dose calculated on a body surface area (mg/sq m) basis for the mid- and high-dose levels, respectively. This finding was not reproduced in two additional rat teratology studies at similar doses.

/GENOTOXICITY/ Orlistat had no detectable mutagenic or genotoxic activity as determined by the Ames test, a mammalian forward mutation assay (V79/HPRT), an in vitro clastogenesis assay in peripheral human lymphocytes, an unscheduled DNA synthesis assay (UDS) in rat hepatocytes in culture, and an in vivo mouse micronucleus test.

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).

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/

Orlistat

Pharmaceutical

Smith, C.D. and Nowell, L.H., 2024. Health-Based Screening Levels for evaluating water-quality data (3rd ed.). DOI:10.5066/F71C1TWP

The half-life of orlistat of the small amount of absorbed orlistat ranges between 1-2 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 hydrolyzed in the intestinal wall. In a radiolabeled orlistat mass balance study in obese patients, two metabolites were identified. The first metabolite, M1, was the hydrolyzed β-lactone ring product of orlistat. The second metabolite, M3, was produced from M1’s cleavage of the N-formyl leucine side-chain. Both metabolites accounted for about 42% of total plasma radioactivity. Both M1 and M3 are considered pharmacologically inactive.

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.

95M8R751W8

ORLISTAT

Established Pharmacologic Class [EPC] - Intestinal Lipase Inhibitor

Mechanisms of Action [MoA] - Lipase Inhibitors

Orlistat is an Intestinal Lipase Inhibitor. The mechanism of action of orlistat is as a Lipase Inhibitor.

ORLISTAT

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.

Agents that increase energy expenditure and weight loss by neural and metabolic regulation.

Substances that alter the metabolism of LIPIDS.

The systemic absorption and exposure of orlistat is low, however, systemic absorption of the drug is not required for orlistat activity. After an oral dose with 360 mg of radiolabeled orlistat, plasma radioactivity achieved a peak at about 8 hours. Plasma concentrations of unchanged parent drug were close to the lower end of detection limits (<5 ng/mL). In plasma samples of patients taking orlistat, the detection of unchanged drug was sporadic and very low concentrations were detected (<10 ng/mL or 0.02 μM) with no evidence suggesting drug accumulation.

After single oral dose of radiolabled orlistat in both normal weight and obese volunteers fecal excretion of the unabsorbed drug was found to be the major route of elimination with <2% urinary excretion. Fecal elimination of orlistat is estimated between 95-97%. Complete excretion by both routes occurs within in 3 to 5 days.

Volume of distribution cannot be obtained because the absorption of orlistat is minimal. Orlistat is minimally distributed to erythrocytes and is primarily bound to proteins.

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.