Orlistat (40 μM; 2 days) invoiced repair proteins by 30-70% in human peripheral blood mononuclear cells, two leukocytes, and another Turkish line, but had no effect on MGMT levels in human melanoma cell lines.

Orlistat (10 mg/kg/day) considerably improved blood lipid profile, upregulated antioxidant enzyme expression and anti-inflammatory marker expression, and downregulated pro-inflammatory marker expression as compared to the nutrition (OB) group [2].

Western Blot analysis [1]
Cell Types: human melanoma cell line M10, peripheral blood mononuclear cells, human Jurkat CD4+ T cell leukemia cell line, human promyelocytic leukemia cell line HL-60. Will Dramatically change MGMT mRNA expression [1]. , epithelial colon cancer HCT116 cells, non-adherent mononuclear cells (NAMNC) [1]
Tested Concentrations: 2.5, 5, 10, 20, 40 μM for Jurkat cells; 20 and 40 μM for HCT116 cells; normal NAMNC, M10 melanoma , 40 μM for HL-60 promyelocytic leukemia and HT-29 colon cancer cells.
Incubation Duration: 2 days for Jurkat cells; 2 or 4 days for HCT116 cells; NAMNC, M10 melanoma, HL-60 promyelocytic leukemia, HT-29 colon cancer 2-day
Experimental Results: For Jurkat cells, MGMT levels were diminished by >50% at a concentration of 40 μM, whereas at lower concentrations, almost no effect was seen. used. MGMT expression in HCT116 cells was downregulated at 40 μM. At a concentration of 40 μM, MGMT levels were diminished by approximately 50% in normal NAMNC, HL-60 promyelocytic leukemia, a

Animal/Disease Models: Eighteen male SD (SD (Sprague-Dawley)) strain rats, aged 8-10 weeks, weighing 200-250 g[2]
Doses: 10 mg/kg/day
Doses: po (po (oral gavage)) Six-week
Experimental Results: Treatment There was a sustained recovery of the gained weight, which was observed Dramatically from the ninth week until the end of the experimental period.

Absorption, Distribution and Excretion
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.
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.

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Metabolism / Metabolites
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.

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Biological Half-Life
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.

Hepatotoxicity
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.
Likelihood score: C (probable rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Orlistat is poorly absorbed orally, but a small amount has been detected in the milk of one woman. It is unlikely that orlistat will be absorbed by the infant in amounts that would adversely affect the breastfed infant. Because it inhibits the absorption of fat-soluble vitamins, mothers using it should take a multivitamin supplement at bedtime.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Orlistat is >99% bound to plasma proteins (mainly lipoproteins and albumin).

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Interactions
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.

[1]. Giorgia Cioccoloni, et al. Influence of fatty acid synthase inhibitor orlistat on the DNA repair enzyme O6-methylguanine-DNA methyltransferase in human normal or malignant cells in vitro. Int J Oncol. 2015 Aug;47(2):764-72.
[2]. Zaidatul Akmal Othman, et al. Anti-Atherogenic Effects of Orlistat on Obesity-Induced Vascular Oxidative Stress Rat Model. Antioxidants (Basel). 2021 Feb 6;10(2):251.

Therapeutic Uses
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/

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Drug Warnings
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.

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Pharmacodynamics
Orlistat helps with weight reduction and maintenance by inhibiting the absorption of dietary fats via the inhibition of lipase enzymes.

C29H53NO5

495.73

495.392

96829-58-2

Orlistat (Standard);96829-58-2

3034010

White to off-white solid powder

1.0±0.1 g/cm3

615.9±30.0 °C at 760 mmHg

<50ºC

326.3±24.6 °C

0.0±1.8 mmHg at 25°C

1.470

8.94

1

5

23

35

579

4

CCCCCCCCCCC[C@@H](C[C@H]1[C@@H](C(=O)O1)CCCCCC)OC(=O)[C@H](CC(C)C)NC=O

AHLBNYSZXLDEJQ-FWEHEUNISA-N

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

[(2S)-1-[(2S,3S)-3-hexyl-4-oxooxetan-2-yl]tridecan-2-yl] (2S)-2-formamido-4-methylpentanoate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.04 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (5.04 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.04 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)