Orlistat (Tetrahydrolipstatin)   中文名称: 奥利司他

奥利司他（40 μM；2 天）使人外周血单核细胞、两种白细胞和另一种土耳其细胞系中的修复蛋白增加 30-70%，但对人黑色素瘤细胞系中的 MGMT 水平没有影响。

与营养（OB）组相比，奥利司他（10 mg/kg/天）显着改善血脂状况，上调抗氧化酶表达和抗炎标志物表达，并下调促炎标志物表达[2]。

Western Blot分析[1]
细胞类型：人黑色素瘤细胞系M10、外周血单核细胞、人Jurkat CD4+ T细胞白血病细胞系、人早幼粒细胞白血病细胞系HL-60。会显着改变 MGMT mRNA 表达 [1]。 、上皮结肠癌 HCT116 细胞、非贴壁单核细胞 (NAMNC) [1]
测试浓度：Jurkat 细胞为 2.5、5、10、20、40 μM； HCT116 细胞为 20 和 40 μM；正常 NAMNC、M10 黑色素瘤，40 μM 用于 HL-60 早幼粒细胞白血病和 HT-29 结肠癌细胞。
孵育时间：Jurkat 细胞为 2 天； HCT116 细胞 2 或 4 天； NAMNC、M10 黑色素瘤、HL-60 早幼粒细胞白血病、HT-29 结肠癌 2 天
实验结果：对于 Jurkat 细胞，MGMT 水平在浓度为 40 μM 时降低 > 50% ，而在较低浓度下，几乎没有看到任何影响。用过的。 HCT116 细胞中的 MGMT 表达在 40 μM 时下调。在 40 μM 浓度下，正常 NAMNC、HL-60 早幼粒细胞白血病、

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).

[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.

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.
The global prevalence of obesity is increasing rapidly. Obesity-related complications lead to significant personal and economic burden by reducing quality of life and increasing the cost of healthcare. In some individuals, diet and exercise are insufficient to maintain weight loss, and pharmacological or surgical intervention is required. Orlistat is a lipase inhibitor used in the treatment of obesity that works by inhibiting fat-metabolizing enzymes. It was approved by the FDA for use in combination with a reduced-calorie diet in 1999. This drug is a generally well-tolerated and effective weight-loss aid and is now available in both over-the-counter and prescription preparations, depending on the dosage quantity.
Orlistat is an Intestinal Lipase Inhibitor. The mechanism of action of orlistat is as a Lipase Inhibitor.
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.
Orlistat has been reported in Camellia sinensis with data available.
Orlistat is a reversible active-site inhibitor of gastrointestinal lipases. Orlistat forms a covalent bond with the active serine site in gastric and pancreatic lipases, thereby inhibiting their activity and preventing dietary fat from being hydrolyzed and absorbed. (NCI04)
A lactone derivative of LEUCINE that acts as a pancreatic lipase inhibitor to limit the absorption of dietary fat; it is used in the management of obesity.

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Drug Indication
Orlistat is indicated for obesity management including weight loss and weight maintenance when used in combination with calorie reduction in overweight and obese adults; this indication applies to both the prescription formulation of 120 mg and the over-the-counter formulation of 60 mg. Orlistat in the 120 mg prescription formulation is also indicated to reduce the risk of weight regain following weight loss.
FDA Label
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.
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.

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Mechanism of Action
Orlistat is a potent and selective inhibitor of various lipase enzymes responsible for the metabolism of fat. It acts in the gastrointestinal (GI) tract via covalent binding to the serine residues located on the active site of both gastric and pancreatic lipase. When orlistat is taken with food containing fat, it partially inhibits the hydrolysis of triglycerides. This decreases absorption of monoaclglycerides and free fatty acids, contributing to weight maintenance and weight loss.
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.

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

81.7

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.04 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: 2.5 mg/mL (5.04 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (5.04 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。