Entacapone（50 μM，48 小时）可增加 Hep-G2 细胞中 mRNA 上 m6A 的数量。它没有表现出对 RNA m6A 去甲基化酶 AlkB 同源物 5 (ALKBH5) 或 10-11 易位甲基胞嘧啶双加氧酶 1 (TET1) 的酶活性的任何抑制作用，也不会改变恩他卡朋处理的 DNA 甲基化或组蛋白甲基化模式Hep-G2细胞[2]。

口服恩他卡朋会产生剂量反应效应（每天 600 毫克/公斤，持续 3-9 周）。三周后，小鼠体重比对照组小鼠低10.1%，食物摄入量相当。恩他卡朋治疗导致脂肪量和脂肪量比下降。用恩他卡朋治疗的小鼠也表现出能量消耗增加，表现为小鼠甘油三酯 (10.2%)、低密度脂蛋白胆固醇 (31.0%) 和总胆固醇 (17.6%) 降低[2]。

Animal/Disease Models: High-fat diet-induced obese (DIO) mouse model[2]
Doses: 600 mg/kg
Route of Administration: Oral administration; 600 mg/kg per day; 3-9 weeks
Experimental Results: Regulated the metabolic disorders in DIO mouse.

Absorption, Distribution and Excretion
Entacapone is rapidly absorbed (approximately 1 hour). The absolute bioavailability following oral administration is 35%.
Entacapone is almost completely metabolized prior to excretion, with only a very small amount (0.2% of dose) found unchanged in urine. As only about 10% of the entacapone dose is excreted in urine as parent compound and conjugated glucuronide, biliary excretion appears to be the major route of excretion of this drug.
20 L
850 mL/min
In rats and in humans, the absolute bioavailability was dose-dependent and ranged from 20% to 55%, following single dose of 10, 65 and 400 mg/kg, in rats and from 29% to 49%, following single dose of 5, 25, 50, 100, 200, 400 and 800 mg, in humans.
Absorption of unchanged entacapone after single oral administration is quite rapid both in rats and in dogs. Two peaks in plasma concentrations, occurring at 5-15 minutes and at 3-5 hours post dose, were found in rats indicating that entacapone is subject to enterohepatic circulation and a single peak at 3 hours was found in dogs. A transformation of entacapone to its (Z)-isomer took place in both species studied, the transformation being minimal in rats but quite noticeable in dogs.
/MILK/ In animal studies, entacapone was excreted into maternal rat milk.
In rats and dogs, entacapone metabolites are predominantly excreted in the feces (two thirds as glucuronide or sulfate conjugates) and one third in the urine with less than 1.5% of the dose as unchanged entacapone. After the first hour 30-45% of the dose was recovered in the bile, with an enterohepatic circulation accounting for about 10% of the given radioactivity.
For more Absorption, Distribution and Excretion (Complete) data for ENTACAPONE (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Metabolized via isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer.
In rats and dogs, entacapone metabolites are predominantly excreted in the feces (two thirds as glucuronide or sulfate conjugates) and one third in the urine with less than 1.5% of the dose as unchanged entacapone. After the first hour 30-45% of the dose was recovered in the bile, with an enterohepatic circulation accounting for about 10% of the given radioactivity.
Entacapone is extensively metabolised in the liver in all species including humans, the main metabolic pathway being glucuronidation, sulfation and isomerisation from (E)- to (Z)-isomer (active metabolite). Similar pathways across species are the reduction of the C-C double bond of the side chain (less important in rat and in man) and the hydrolysis to 3,4-dihydroxy-5-nitrobenzaldehyde. The dissimilarities consists of amide N-dealkylation, nitro reduction and O-methylation (only in rats), amide hydrolysis and nitrile hydrolysis (only in dogs) and oxidative hydrolysis of one of the ethyl groups of the diethylamide group (only in man).
Entacapone is almost completely metabolized prior to excretion, with only a very small amount (0.2% of dose) found unchanged in urine. The main metabolic pathway is isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer; the glucuronide conjugate is inactive.
Entacapone undergoes extensive metabolism, mainly in the liver. The main metabolic pathway of entacapone in humans is the isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer; the glucuronide conjugate is inactive.
Entacapone has known human metabolites that include Entacapone 3-o-glucuronide.
Metabolized via isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer.
Route of Elimination: Entacapone is almost completely metabolized prior to excretion, with only a very small amount (0.2% of dose) found unchanged in urine. As only about 10% of the entacapone dose is excreted in urine as parent compound and conjugated glucuronide, biliary excretion appears to be the major route of excretion of this drug.
Half Life: 0.4-0.7 hour

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Biological Half-Life
0.4-0.7 hour
The elimination of entacapone is biphasic, with an elimination half-life of 0.4 hour to 0.7 hour based on the beta-phase and 2.4 hours based on the gamma-phase.
The overall elimination half-life of entacapone ranged from 30 minutes to 1 hour in dogs and from 1.5 to 3 hours in man.

Toxicity Summary
IDENTIFICATION AND USE: Entacopone, a selective and reversible inhibitor of catechol-O-methyl-transfersase (COMT) is used as an adjunct to levodopa and carbidopa to treat end-of-dose "wearing-off" in patients with Parkinson's disease. HUMAN EXPOSURE AND TOXICITY: The postmarketing data include several cases of overdose. The highest reported dose of entacapone was at least 40,000 mg. The acute symptoms and signs commonly seen in these cases included somnolence and decreased activity, states related to depressed level of consciousness (coma, confusion and disorientation) and discolorations of skin, tongue, and urine, as well as restlessness, agitation, and aggression. Catechol-O-methyltransferase (COMT) inhibition by entacapone treatment is dose-dependent. A massive overdose of entacapone may theoretically produce a 100% inhibition of the COMT enzyme in humans, thereby preventing the metabolism of endogenous and exogenous catechols. Postmarketing reports also indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during entacapone treatment or after starting or increasing the dose of entacapone. Therefore, patients with a major psychotic disorder should ordinarily not be treated with entacapone because of the risk of exacerbating psychosis. Entacapone was clastogenic in cultured human lymphocytes in the presence of metabolic activation. ANIMAL STUDIES: Rats were treated for two years with entacapone at daily doses of 20, 90, or 400 mg/kg by oral gavage. An increased incidence of renal tubular adenomas and carcinomas was found in male rats treated with the highest dose. Reproduction studies have been performed in rats and rabbits at doses up to 1000 mg/kg/day and 300 mg/kg/day, respectively, of entacapone. Increased incidence of fetal variations was evident in litters from rats treated at the highest dose in the absence of overt maternal toxicity. Increased frequencies of abortion and late/total resorptions and decreased fetal weights were observed in litters of rabbits treated with maternotoxic doses of 100 mg/kg/day or greater. There was no evidence of teratogenicity in these studies. When entacapone was administered to female rats prior to mating and during early gestation, an increased incidence of fetal eye anomalies (macrophthalmia, microphthalmia, and anophthalmia) was observed in litters of dams treated with doses of 160 mg/kg/day or greater, in the absence of maternal toxicity. Administration of up to 700 mg/kg/day to female rats during the latter part of gestation and throughout lactation produced no evidence of developmental impairments in the offspring. Entacapone did not impair fertility or general reproductive performance in rats treated with up to 700 mg/kg/day. Delayed mating, but no fertility impairment, was evident in female rats treated with 700 mg/kg/day of entacapone. Entacapone was mutagenic and clastogenic in the in vitro mouse lymphoma tk assay in the presence and absence of metabolic activation. Entacapone, either alone or in combination with levodopa and carbidopa, was not clastogenic in the in vivo mouse micronucleus test or mutagenic in the bacterial reverse mutation assay (Ames test).
The mechanism of action of entacapone is believed to be through its ability to inhibit COMT in peripheral tissues, altering the plasma pharmacokinetics of levodopa. When entacapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are greater and more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that at a given frequency of levodopa administration, these more sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to a greater reduction in the manifestations of parkinsonian syndrome.

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Hepatotoxicity
Entacapone therapy has been associated with serum aminotransferase elevations (above 3 times the upper limit of normal) in only 0.3% to 0.5% of patients, which is similar or minimally higher than the rate in subjects receiving placebo. The elevations were usually transient and asymptomatic and rarely required dose adjustment. In preliminary clinical trials, there were no reports of clinically apparent serious liver injury with jaundice. Subsequently, isolated instances of hepatotoxicity have been reported to the sponsor, injury arising 2 to 6 weeks after starting entacapone with mild jaundice and cholestatic pattern of liver enzyme elevations, and rapid recovery on stopping. Immunoallergic and autoimmune features were not present. The clinical phenotype of injury and associated features have not been reported in any detail. Thus, entacapone may rarely cause clinically apparent liver injury, but it has not been associated with the severe hepatitis and acute liver failure that characterized cases of tolcapone induced liver injury.
Likelihood score: D (possible, rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of entacapone during breastfeeding. An alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ 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
98% (bind to serum albumin)

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Interactions
As most entacapone excretion is via the bile, caution should be exercised when drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidase are given concurrently with entacapone. These include probenecid, cholestyramine, and some antibiotics (e.g., erythromycin, rifampicin, ampicillin, and chloramphenicol).
Entacapone is highly protein bound (98%). In vitro studies have shown no binding displacement between entacapone and other highly bound drugs, such as warfarin, salicylic acid, phenylbutazone, and diazepam.
Potential pharmacokinetic interaction (decreased entacapone excretion) with drugs interfering with biliary excretion, glucuronidation, and intestinal beta-glucuronidase (e.g., cholestyramine, probenecid, some anti-infectives (e.g., ampicillin, chloramphenicol, erythromycin, rifampin)).
Potential pharmacologic interaction (inhibits catecholamine metabolism) with nonselective monoamine oxidase (MAO) inhibitors (e.g., phenelzine, tranylcypromine). Pharmacologic interaction unlikely with selective MAO-B inhibitors (e.g., selegiline).
For more Interactions (Complete) data for ENTACAPONE (13 total), please visit the HSDB record page.

[1]. Biochemical and pharmacological properties of a peripherally acting catechol-O-methyltransferase inhibitor entacapone. Naunyn Schmiedebergs Arch Pharmacol. 1992 Sep;346(3):262-6.

[2]. Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1. Sci Transl Med.

Therapeutic Uses
Antiparkinson Agents; Enzyme Inhibitors
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health(NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Entacapone is included in the database.
Comtan is indicated as an adjunct to levodopa and carbidopa to treat end-of-dose "wearing-off" in patients with Parkinson's disease. /Included in US product label/
Stalevo, a combination drug consisting of levodopa, carbidopa (dopa decarboxylase inhibitor), and entacapone (catechol-O-methyltransferase-COMT inhibitor) is indicated for the treatment of Parkinson's disease. Stalevo can be used: to substitute (with equivalent strengths of each of the three components) carbidopa/levodopa and entacapone previously administered as individual products. To replace carbidopa/levodopa therapy (without entacapone) when patients experience the signs and symptoms of end-of-dose "wearing-off" and when they have been taking a total daily dose of levodopa of 600 mg or less and have not been experiencing dyskinesias. /Included in US product label/
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a variety of motor symptoms including freezing of gait (FOG), in which walking is transiently halted as if the patient's feet were 'glued to the ground'. Treatment of FOG is still challenging. Although L-threo-3,4-dihydroxyphenylserine (L-DOPS), a precursor of noradrenaline, has been on the market in Japan because of its beneficial effect for FOG, clinical use of L-DOPS has been far from satisfying. However, the fact that there were some responders to L-DOPS encouraged us to hypothesize that the enhancement of L-DOPS concentration in the brain by the co-administration of L-DOPS and a catechol-O-methyl transferase (COMT) inhibitor, which is expected to interrupt L-DOPS metabolism in the peripheral circulation, would be beneficial for FOG. Based on our hypothesis, we conducted a preliminary study with a small number of participants with FOG. Of the 16 PD patients with FOG who completed this study, group 1 (n=6) received L-DOPS co-administered with entacapone, which is a COMT inhibitor used worldwide as an anti-parkinson drug, group 2 (n=5) received entacapone alone, and group 3 (n=5) received L-DOPS alone. Only the patients in group 1 showed a significant improvement in FOG. Moreover, the beneficial effect was observed only in patients with levodopa-resistant FOG. This result supports our hypothesis, at least in patients with levodopa-resistant FOG, and shows that the co-administration of L-DOPS and entacapone could be a new strategy for FOG treatment.

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Drug Warnings
Diarrhea was reported in 10% of patients receiving entacapone in clinical studies, and about 2% of patients required discontinuance of the drug because of diarrhea. Diarrhea generally was of mild to moderate intensity, but severe diarrhea, which required hospitalization, may occur rarely. Diarrhea generally occurs during the first 4-12 weeks of entacapone therapy, but may occur as early as the first week or as late as several months following initiation of entacapone therapy. Diarrhea generally resolved following discontinuance of the drug.
Findings from an FDA-conducted meta-analysis suggest that patients receiving combined therapy with levodopa, carbidopa, and entacapone may be at increased risk of cardiovascular events (i.e., myocardial infarction, stroke, cardiovascular death) compared with those receiving levodopa-carbidopa. The meta-analysis combined cardiovascular-related findings from 15 clinical trials that compared the combination of levodopa, carbidopa, and entacapone with levodopa-carbidopa and found a small but statistically significant increase in the risk of cardiovascular events in those receiving the levodopa, carbidopa, and entacapone regimen (relative risk: 2.46). However, the increased risk was driven largely by data from a single trial (STRIDE-PD); when this trial was removed from the analysis, the results were no longer significant. Various factors make it difficult to draw firm conclusions from this meta-analysis. Many of the trials included in the analysis had a duration of less than 6 months (possibly not long enough to detect cardiovascular risk) and were not specifically designed to evaluate cardiovascular safety. In addition, the majority of patients had preexisting cardiovascular risk factors. At this time, FDA has not concluded that combined therapy with levodopa, carbidopa, and entacapone is associated with an increased risk of cardiovascular events and is continuing to review the available data related to this safety concern. Patients currently receiving entacapone as an adjunct to levodopa-carbidopa (either separately or as a fixed-combination preparation) should continue to take the drugs as prescribed unless otherwise instructed by a clinician. Cardiac function should be monitored regularly in such patients, particularly in those with a history of cardiovascular disease.
Dopaminergic therapy in Parkinson's disease patients has been associated with orthostatic hypotension. Entacapone enhances levodopa bioavailability and, therefore, might be expected to increase the occurrence of orthostatic hypotension. In controlled studies, approximately 1.2% and 0.8% of 200 mg entacapone and placebo patients, respectively, reported at least one episode of syncope. Reports of syncope were generally more frequent in patients in both treatment groups who had an episode of documented hypotension.
Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during Comtan treatment or after starting or increasing the dose of Comtan. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. Abnormal thinking and behavior can cause paranoid ideation, delusions, hallucinations, confusion, disorientation, aggressive behavior, agitation, and delirium. Psychotic-like behaviors were also observed during the clinical development of Comtan. Patients with a major psychotic disorder should ordinarily not be treated with Comtan because of the risk of exacerbating psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of Comtan.
For more Drug Warnings (Complete) data for ENTACAPONE (22 total), please visit the HSDB record page.

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Pharmacodynamics
Entacapone is structurally and pharmacologically related to tolcapone, but unlike tolcapone, is not associated with hepatotoxicity. Entacapone is used in the treatment of Parkinson’s disease as an adjunct to levodopa/carbidopa therapy. Entacapone selectively and reversiblly inhibits catechol-O-methyltransferase (COMT). In mammals, COMT is distributed throughout various organs with the highest activities in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells and neuronal tissues, especially in glial cells. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, and epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. COMT is responsible for the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa, catalyzing the it to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery.

C14H15N3O5

305.29

305.101

130929-57-6

Entacapone-d10;1185241-19-3;(Z)-Entacapone-d10;Entacapone sodium salt;1047659-02-8;(E)-Entacapone-d10

5281081

Light yellow to yellow solid powder

1.4±0.1 g/cm3

526.6±50.0 °C at 760 mmHg

162-1630C

272.3±30.1 °C

0.0±1.4 mmHg at 25°C

1.642

2.38

130.38

2

6

4

22

500

0

CCN(CC)C(=O)/C(=C/C1=CC(=C(C(=C1)O)O)[N+](=O)[O-])/C#N

JRURYQJSLYLRLN-BJMVGYQFSA-N

InChI=1S/C14H15N3O5/c1-3-16(4-2)14(20)10(8-15)5-9-6-11(17(21)22)13(19)12(18)7-9/h5-7,18-19H,3-4H2,1-2H3/b10-5+

(E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylacrylamide

OR 611; OR611; OR-611; Comtan; Entacapone; HSDB-8251; HSDB8251; HSDB 8251;

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)

DMSO: 61 mg/mL (199.8 mM) Water:<1 mg/mL Ethanol: 2 mg/mL (6.5 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (8.19 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 (8.19 mM) 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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配方 3 中的溶解度: ≥ 2.08 mg/mL (6.81 mM) (饱和度未知) 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), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 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 4 中的溶解度: 1 mg/mL (3.28 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶 (<60°C).

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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;
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7、 以上所有助溶剂都可在 Invivochem.cn网站购买。