美沙酮 | 76-99-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 美沙酮
• 中文别名: 阿米酮
• 英文名称: Methadone
• 英文别名: methadon；racemic methadone；6-(dimethylamino)-4,4-diphenylheptan-3-one
• CAS: 76-99-3
• 化学式: C₂₁H₂₇NO
• 分子量: 309.451
• InChiKey: USSIQXCVUWKGNF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  23
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  20.3
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

代谢

美沙酮在首次通过肝脏时会发生相当广泛的代谢。细胞色素P450酶，主要是CYP3A4、CYP2B6和CYP2C19，以及较少程度的CYP2C9、CYP2C8和CYP2D6，负责将美沙酮转化为EDDP（2-乙基-1,5-二甲基-3,3-二苯基吡咯烷）和其他无活性代谢物，这些代谢物主要通过尿液排出。美沙酮首先经历N-去甲基化，形成一个高度不稳定的化合物，通过环化和脱水自发转化为EDDP。EDDP然后转化为2-乙基-5-甲基-3,3-二苯基-1-吡咯烷（EDMP）。EDDP和EDMP都是无活性的。CYP同种酶也对代谢美沙酮对映异构体表现出不同的亲和力：CYP2C19、CYP3A7和CYP2C8优先代谢（R）-美沙酮，而CYP2B6、CYP2D6和CYP2C18优先代谢（S）-美沙酮。CYP3A4没有对映异构体偏好。细胞色素P450酶中的单核苷酸多态性（SNPs）可能会影响美沙酮的药代动力学，并导致对美沙酮治疗反应的个体间差异。特别是，CYP2B6多态性已被证明影响个体对美沙酮的反应，因为它是美沙酮N-去甲基化、清除和代谢比[methadone]/[EDDP]的主要决定因素。SNPs CYP2B6*6、*9、*11、CYP2C19*2、*3、CYP3A4*1B和CYP3A5*3导致美沙酮血浆浓度增加，N-去甲基化减少和美沙酮清除减少，而CYP2B6*6/*6纯合子携带者显示美沙酮的代谢和清除减弱。有关更多信息，请参阅药物基因组学部分。 药物基因组学对CYP酶的影响可能是显著的，因为美沙酮的长半衰期可能导致一些个体的血药水平高于正常治疗水平，这使他们有剂量相关副作用的风险。例如，(R)-美沙酮水平升高可能会增加呼吸抑制的风险，而(S)-美沙酮水平升高可能会增加由于QTc间期延长而导致严重心律失常的风险。

Methadone undergoes fairly extensive first-pass metabolism. Cytochrome P450 enzymes, primarily CYP3A4, CYP2B6, and CYP2C19 and to a lesser extent CYP2C9, CYP2C8, and CYP2D6, are responsible for conversion of methadone to EDDP (2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine) and other inactive metabolites, which are excreted mainly in the urine. Methadone first undergoes N-demethylation to form a highly unstable compound that spontaneously converts to EDDP through cyclization and dehydration. EDDP is then converted to 2-ethyl5-methyl-3,3-diphenyl-1-pyrroline (EDMP). Both EDDP and EDMP are inactive. The CYP isozymes also demonstrate different affinities for metabolizing the different methadone enantiomers: CYP2C19, CYP3A7, and CYP2C8 preferentially metabolize (R)-methadone while CYP2B6, CYP2D6, and CYP2C18 preferentially metabolize (S)-methadone. CYP3A4 does not have an enantiomer preference. Single nucleotide polymorphisms (SNPs) within the cytochrome P450 enzymes can impact methadone pharmacokinetics and contribute to the interindividual variation in response to methadone therapy. In particular, CYP2B6 polymorphisms have been shown to impact individual response to methadone as it is the predominant determinant involved in the N-demethylation of methadone, clearance, and the metabolic ratios of [methadone\]/[EDDP]. The SNPs CYP2B6\*6, \*9, \*11, CYP2C19\*2, \*3, CYP3A4\*1B, and CYP3A5\*3 result in increased methadone plasma concentrations, decreased N-demethylation, and decreased methadone clearance, while homozygous carriers of CYP2B6\*6/\*6 demonstrate diminished metabolism and clearance of methadone. See the pharmacogenomics section for further information. Pharmacogenomic effects on the CYP enzymes can be significant as the long half-life of methadone can result in some individuals having higher than normal therapeutic levels which puts them at risk of dose-related side effects. For example, elevated (R)-methadone levels can increase the risk of respiratory depression, while elevated (S)-methadone levels can increase the risk of severe cardiac arrhythmias due to prolonged QTc interval.

来源:DrugBank

代谢

使用液相色谱/串联质谱法测定了死后外周血液和肝脏组织中美沙酮及其两种代谢物（2-乙基亚烯-1,5-二甲基-3,3-二苯基吡咯烷和2-乙基-5-甲基-3,3-二苯基吡咯啉）的浓度和比值。这些分析采用了氘代内标和多反应监测（MRM）技术。每个分析物的线性范围为0.01-2.0毫克/升。在46例美沙酮阳性案件中，测定了肝脏和外周血液中的美沙酮、2-乙基亚烯-1,5-二甲基-3,3-二苯基吡咯烷和2-乙基-5-甲基-3,3-二苯基吡咯啉。无论血液还是肝脏，所有标本中都检测到了美沙酮和2-乙基亚烯-1,5-二甲基-3,3-二苯基吡咯烷。2-乙基-5-甲基-3,3-二苯基吡咯啉仅在肝脏中检测到，仅在17个案例中，其浓度远低于2-乙基亚烯-1,5-二甲基-3,3-二苯基吡咯烷。在2-乙基-5-甲基-3,3-二苯基吡咯啉阳性案例的血液和肝脏中美沙酮和2-乙基亚烯-1,5-二甲基-3,3-二苯基吡咯烷的浓度范围高于阴性案例，但有重叠。这些数据表明，尽管美沙酮在体内很容易被去甲基化和环化成2-乙基亚烯-1,5-二甲基-3,3-二苯基吡咯烷，但转化为2-乙基-5-甲基-3,3-二苯基吡咯啉的效率可能较低，且其在死后组织中的积累可能高度个体化。

... The drug/metabolite concentrations and ratios of methadone to two of its metabolites (2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine; and 2-ethyl-5-methyl-3,3-diphenylpyrroline) in postmortem peripheral blood and liver tissue by liquid chromatography/tandem mass spectrometry /were determined/. The assays employed deuterated internal standards and multiple reaction monitoring (MRM) techniques. The assay linear range was 0.01-2.0 mg/L for each analyte. Methadone, 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine, and 2-ethyl-5-methyl-3,3-diphenylpyrroline were determined in liver and peripheral blood from 46 methadone-positive cases. Methadone and 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine were detected in all specimens, whether blood or liver. 2-ethyl-5-methyl-3,3-diphenylpyrroline was detected, only in liver, and only 17 cases, at concentrations much lower than those of 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine. Concentrations of methadone and 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine in blood and liver from 2-ethyl-5-methyl-3,3-diphenylpyrroline-positive cases were in ranges higher than, but overlapping with, concentrations in blood and liver from 2-ethyl-5-methyl-3,3-diphenylpyrroline-negative cases. These data suggest that although methadone is readily demethylated and cyclized to 2-ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine, in vivo, conversion to 2-ethyl-5-methyl-3,3-diphenylpyrroline may be less efficient and its accumulation in postmortem tissues may be highly individual.

来源:Hazardous Substances Data Bank (HSDB)

代谢

美沙酮在体内被广泛代谢，主要通过肝脏和/或肠道的细胞色素P-450（CYP）同工酶3A4，尽管其他同工酶，包括CYP2B6、CYP1A2和CYP2D6也可能参与。该药物经历N-去甲基化，生成一个无活性的代谢物，2-乙基idene-1,5-二甲基-3,3-二苯基吡咯烷（EDDP）以及其他具有很少或无药理活性的代谢物。尽管美沙酮似乎是P-糖蛋白转运系统的底物，但其药代动力学似乎并未因P-糖蛋白的多态性或抑制而有显著改变。

Methadone is extensively metabolized, principally by cytochrome P-450 (CYP) isoenzyme 3A4 in the liver and/or intestine, although other isoenzymes, including CYP2B6, CYP1A2, and CYP2D6, also may be involved. The drug undergoes N-demethylation to an inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidene (EDDP), and other metabolites with little or no pharmacologic activity. Although methadone appears to be a substrate of the P-glycoprotein transport system, its pharmacokinetics do not appear to be substantially altered by P-glycoprotein polymorphism or inhibition.

来源:Hazardous Substances Data Bank (HSDB)

代谢

代谢通过肝脏的CYP3A4 N-去甲基化进行，原形药物（21%）和代谢物通过尿液排出。胆汁、粪便和汗液中也可以检测到较小量的药物。

Metabolism is via hepatic CYP3A4 N-demethylation, with excretion of the parent (21%) and metabolites in the urine. Smaller amounts are also detectable in the bile, feces, and sweat.

来源:Hazardous Substances Data Bank (HSDB)

代谢

这项研究的目标是确定早产胎盘中代谢美沙酮的酶。从早产（17至34周）胎盘中获得了微粒体组分（共36个，每个胎龄组12个），并测定了它们将美沙酮代谢为2-乙基亚烯-1,5-二甲基-3,3-二苯基吡咯烷（EDDP）的活性。通过使用针对各种细胞色素P450同工酶的化学抑制剂和针对它们制备的单克隆抗体，确定了催化该反应的酶。微粒体对美沙酮的代谢显示出饱和动力学。美沙酮通过芳香化酶去甲基化为EDDP。美沙酮对芳香化酶的亲和力（表观Km）随妊娠期不变，但酶的活性（Vmax）增加，并且在个体胎盘之间差异很大。芳香化酶/CYP19是孕期代谢美沙酮的胎盘酶。个体间酶活性的差异应反映在胎儿循环中美沙酮的浓度上，这可能是影响新生儿戒断综合征发病率和严重程度的一个因素。

The objective of this study was to identify the enzyme that metabolizes methadone in preterm placentas. Microsomal fractions were obtained from preterm (17 to 34 weeks) placentas (36 total; 12 per each gestational age group) and their activity in metabolizing methadone to 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) was determined. The enzyme catalyzing the reaction was identified by using chemical inhibitors selective for various cytochrome P450 isozymes and monoclonal antibodies raised against them. The metabolism of methadone by microsomes revealed saturation kinetics. Methadone was N-demethylated to EDDP by aromatase. The affinity of methadone to aromatase (apparent Km) did not change with gestation, but the activity of the enzyme (Vmax) increased and varied widely between individual placentas. Aromatase/CYP19 is the placental enzyme metabolizing methadone during pregnancy. The variability in enzyme activity among individuals should be reflected by the concentration of methadone in the fetal circulation and might be one of the factors affecting the incidence and intensity of neonatal abstinence syndrome.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：美沙酮是一种二级受控物质。美沙酮盐酸片剂用于阿片类药物成瘾（海洛因或其他类似吗啡的药物）的脱毒治疗，以及与适当的社会和医疗服务相结合的阿片类药物成瘾的维持治疗。美沙酮盐酸片剂还用于治疗足够严重的疼痛，需要每天24小时长期阿片类药物的治疗，且替代治疗选择不足。美沙酮可以用作狗或猫的替代阿片类药物的预处理或镇痛剂。它还正在研究中，用于马的硬脊膜外使用。口服生物利用度差，狗不宜口服给药。人类研究：美沙酮的峰值呼吸抑制效果出现较晚，且持续时间长于峰值镇痛效果，特别是在初始给药期间。治疗期间发生了QT间期延长和严重的心律失常（尖端扭转型室性心动过速）。大多数病例涉及接受大剂量、每日多次美沙酮治疗的疼痛患者，尽管也有报告称在接受用于阿片类药物成瘾维持治疗的常规剂量治疗的患者中发生了病例。急性过量会产生阿片类药物中毒的迹象，循环和CNS抑制，嗜睡，昏迷，呼吸抑制，以及肠梗阻的胃肠道动力下降。在严重中毒时，可能会出现呼吸暂停、低血压、心动过缓、非心源性肺水肿、癫痫、心律失常和死亡。在评估错误的美沙酮维持诱导期间，以及在维持治疗期间将几天的剂量合并时，可能会发生死亡。意外摄入后也可能会死亡。对10名药物依赖性母亲的新生儿在子宫内暴露于滥用药物对某些神经和行为特征的影响进行了研究。14名未接受药物的母亲的新生儿作为匹配的对照组。在胎儿期暴露于滥用药物的新生儿表现出高度觉醒和易怒，以及极端的肌肉张力波动，主要表现为过度紧张（僵直）与短暂的非常低张力（弛缓）交替。这些新生儿也非常活跃，颤抖，运动不成熟，并且表现出几乎不断的哭泣和睡眠模式紊乱。长期使用阿片类药物可能会降低女性和有生育潜力的男性的生育能力。目前尚不清楚这些对生育能力的影响是否可逆。美沙酮治疗可能会降低人类男性的生殖功能。据报道，接受美沙酮治疗的个体精液量、精囊和前列腺分泌物减少。此外，还报告了血清睾酮水平降低、精子活力下降和精子形态异常。动物研究：过量可能会在大多数物种中产生深度的呼吸和/或CNS抑制。新生儿可能比成年动物更易受到这些影响。其他有毒效应可能包括心血管崩溃、低体温和骨骼肌张力下降。在雄性大鼠交配前给予美沙酮，导致与未接触美沙酮的雌性后代在断奶后体重增加减少。雄性后代表现出胸腺重量减轻，而雌性后代表现出肾上腺重量增加。对这些雄性和雌性后代的行为测试表明，与对照组动物相比，行为测试有显著差异。染色体分析显示，在1毫克/千克/天或更高剂量下，染色体异常的频率剂量依赖性增加。在怀孕小鼠中，从妊娠第6天到第15天皮下注射高达28毫克/千克/天的美沙酮，没有引起畸形，但在10毫克/千克/天或更高剂量下，着床后损失增加，活胎儿减少，在20毫克/千克/天或更高剂量下，骨化减少和胎儿体重减轻。美沙酮在体内小鼠显性致死试验和体内哺乳动物精原细胞染色体畸变试验中呈阳性。此外，美沙酮在大肠杆菌DNA修复系统、脉孢菌和小鼠淋巴瘤正向突变试验中也呈阳性。相比之下，美沙酮在果蝇生殖细胞染色体断裂和分离以及性连锁隐性致死基因突变的测试中呈阴性。

IDENTIFICATION AND USE: Methadone is a Schedule II controlled substance. Methadone hydrochloride tablets are indicated for the detoxification treatment of opioid addiction (heroin or other morphine-like drugs), and for maintenance treatment of opioid addiction, in conjunction with appropriate social and medical services. Methadone hydrochloride tablets are also indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Methadone may be used as an alternative opioid preanesthetic or analgesic in dogs or cats. It is also being investigated for epidural use for horses. Poor oral bioavailability precludes oral dosing in dogs. HUMAN STUDIES: The peak respiratory depressant effect of methadone occurs later, and persists longer than the peak analgesic effect, especially during the initial dosing period. QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred during treatment with methadone. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Acute overdosage produces signs of opioid toxicity, circulatory and CNS depression, lethargy, coma, respiratory depression, and decreased GI motility with ileus. Apnea, hypotension, bradycardia, noncardiogenic pulmonary edema, seizures, dysrhythmias, and death may occur with severe poisonings. Death may occur during induction of methadone maintenance when tolerance is incorrectly assessed, and during maintenance when several days' doses are combined. Death can also follow accidental ingestion. The effect of in utero exposure to drugs of abuse on certain neurological and behavioral characteristics of the newborn was studied in 10 infants of drug-dependent mothers. Fourteen newborns of mothers not receiving drugs served as matched controls. Infants exposed to drugs of abuse during fetal life exhibited a high level of arousal and irritability, and extreme muscle tone fluctuations, a predominant hypertonicity (rigidity) alternating with short periods of a very low tone (flaccidity). These newborns were also highly active, tremulous, and motorically immature, and displayed near-constant crying and disturbed sleep patterns. Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible. Reproductive function in human males may be decreased by methadone treatment. Reductions in ejaculate volume and seminal vesicle and prostate secretions have been reported in methadone-treated individuals. In addition, reductions in serum testosterone levels and sperm motility, and abnormalities in sperm morphology have been reported. ANIMAL STUDIES: Overdosage may produce profound respiratory and/or CNS depression in most species. Newborns may be more susceptible to these effects than adult animals. Other toxic effects can include cardiovascular collapse, hypothermia, and skeletal muscle hypotonia. Methadone administered to the male rat prior to mating with methadone-naive females resulted in decreased weight gain in progeny after weaning. The male progeny demonstrated reduced thymus weights, whereas the female progeny demonstrated increased adrenal weights. Behavioral testing of these male and female progeny revealed significant differences in behavioral tests compared to control animals. Chromosome analysis revealed a dose-dependent increase in the frequency of chromosomal abnormalities at 1 mg/kg/day or greater. In pregnant mice, subcutaneous doses up to 28 mg/kg/day methadone administered from Gestation Day 6 to 15 resulted in no malformations, but there were increased postimplantation loss and decreased live fetuses at 10 mg/kg/day or greater and decreased ossification and fetal body weight at 20 mg/kg/day or greater. Methadone tested positive in the in vivo mouse dominant lethal assay and the in vivo mammalian spermatogonial chromosome aberration test. Additionally, methadone tested positive in the E. coli DNA repair system and Neurospora crassa and mouse lymphoma forward mutation assays. In contrast, methadone tested negative in tests for chromosome breakage and disjunction and sex-linked recessive lethal gene mutations in germ cells of Drosophila using feeding and injection procedures.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

美沙酮是一种μ-激动剂；一种合成阿片类镇痛药，其多种作用在性质上与吗啡相似，其中最突出的是涉及中枢神经系统和由平滑肌组成的器官。美沙酮的主要治疗用途是用于镇痛以及在阿片类药物成瘾中进行戒毒或维持治疗。美沙酮戒断综合症虽然在性质上与吗啡相似，但不同之处在于其发作较慢，病程较长，症状较轻。一些数据还表明，美沙酮在N-甲基-D-天冬氨酸（NMDA）受体上起到拮抗剂的作用。NMDA受体拮抗作用对美沙酮疗效的贡献尚不清楚。其他NMDA受体拮抗剂已在动物中显示出神经毒性效应。

Methadone is a mu-agonist; a synthetic opioid analgesic with multiple actions qualitatively similar to those of morphine, the most prominent of which involves the central nervous system and organs composed of smooth muscle. The principal therapeutic uses for methadone are for analgesia and for detoxification or maintenance in opioid addiction. The methadone abstinence syndrome, although qualitatively similar to that of morphine, differs in that the onset is slower, the course is more prolonged, and the symptoms are less severe. Some data also indicate that methadone acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor. The contribution of NMDA receptor antagonism to methadone's efficacy is unknown. Other NMDA receptor antagonists have been shown to produce neurotoxic effects in animals.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

美沙酮治疗尚未与血清酶水平升高或特异质急性、临床上明显的肝损伤相关联。然而，慢性乙型肝炎和丙型肝炎在维持美沙酮治疗的人群中很常见。没有证据表明美沙酮维持治疗会加慢性病毒性肝炎的病程。在前瞻性研究中，短暂血清酶水平升高在维持美沙酮治疗的患者中并不少见；然而，几乎所有异常都发生在有慢性乙型肝炎或丙型肝炎基础的患者中，并且在治疗期间没有新的临床上明显的肝损伤发生。 关于美沙酮的安全性和潜在肝毒性的参考资料，请参见“阿片类药物”概述部分。 药物类别：阿片类药物

Therapy with methadone has not been linked to serum enzyme elevations or to idiosyncratic acute, clinically apparent liver injury. However, chronic hepatitis B and C are common among persons on methadone maintenance. There is no evidence that methadone maintenance worsens the course of chronic viral hepatitis. In prospective studies, transient serum enzyme elevations were not uncommon in patients on methadone maintenance; however, almost all of the abnormalities occurred in patients with underlying chronic hepatitis B or C and no clinically apparent liver injury arose anew during therapy. References on the safety and potential hepatotoxicity of methadone are given in the Overview section of the Opioids. Drug Class: Opioids

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：美沙酮

Compound:methadone

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI标注：模糊的DILI关注

DILI Annotation:Ambiguous DILI-concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 吸收

美沙酮是一种脂溶性较高的阿片类药物，能够很好地从胃肠道吸收。口服美沙酮后，生物利用度在36-100%之间，个体间差异显著。给药后15-45分钟就能在血液中检测到美沙酮，血药浓度峰值在1到7.5小时之间达到。在给药后约4小时可以观察到第二个峰，这可能是由于肠肝循环。美沙酮的药代动力学剂量比例关系尚不清楚。每日口服剂量在10到225毫克之间时，稳态血药浓度在65到630 ng/mL之间，峰值浓度在124到1255 ng/mL之间。食物对美沙酮生物利用度的影响尚未评估。与健康受试者相比，阿片类药物使用者吸收较慢，这可能反映了阿片类药物在减缓胃排空和移动性方面的药理作用。由于美沙酮在药代动力学和药效学方面个体间差异很大，治疗应该针对每个患者进行个性化。对于给定剂量的美沙酮，血药浓度个体间差异可达17倍，这可能是由于CYP酶功能个体差异所致。美沙酮的立体异构体之间在药代动力学上也有很大的变异性，这进一步复杂化了药代动力学的解释和研究。

Methadone is one of the more lipid-soluble opioids and is well absorbed from the gastrointestinal tract. Following oral administration of methadone, bioavailability ranges from 36-100%, with a marked interindividual variation. It can be detected in blood as soon as 15-45 minutes following administration with peak plasma concentrations achieved between 1 to 7.5 hours. A second peak is observed ~4 hours after administration and is likely due to enterohepatic circulation. Dose proportionality of methadone pharmacokinetics is not known. Following administration of daily oral doses ranging from 10 to 225 mg the steady-state plasma concentrations ranged between 65 to 630 ng/mL and the peak concentrations ranged between 124 to 1255 ng/mL. Effect of food on the bioavailability of methadone has not been evaluated. Slower absorption is observed in opioid users compared to healthy subjects, which may reflect the pharmacological effect of opioids in slowing gastric emptying and mobility. Due to the large inter-individual variation in methadone pharmacokinetics and pharmacodynamics, treatment should be individualized to each patient. There was an up to 17-fold interindividual variation found in methadone blood concentrations for a given dosage, likely due in part to individual variability in CYP enzyme function. There is also a large variability in pharmacokinetics between methadone's enantiomers, which further complicates pharmacokinetic interpretation and study.

来源:DrugBank

吸收、分配和排泄

• 消除途径

美沙酮的消除是通过广泛的生物转化介导的，随后通过肾脏和粪便排泄。未代谢的美沙酮及其代谢物以不同程度通过尿液排出。

The elimination of methadone is mediated by extensive biotransformation, followed by renal and fecal excretion. Unmetabolized methadone and its metabolites are excreted in urine to a variable degree.

来源:DrugBank

吸收、分配和排泄

• 分布容积

由于个体间药物动力学的差异，对美沙酮分布容积的估计范围从189-470升，而药品说明书将其列在1.0-8.0升/公斤之间。由于这个数值高于生理总体积的水，美沙酮在体内高度分布，包括大脑、肠道、肾脏、肝脏、肌肉和肺。一项群体药代动力学研究发现，受试者的性别和体重解释了大约33%的美沙酮表观分布容积的变异。美沙酮被发现分泌在唾液、汗液、母乳、羊水和脐带血浆中。脐带血中的浓度大约是母体水平的一半。

Due to interindividual differences in pharmacokinetics, estimates of methadone's volume of distribution have ranged from 189-470 L with monographs listing it between 1.0-8.0L/kg. As this is higher than physiological volumes of total body water, methadone is highly distributed in the body including brain, gut, kidney, liver, muscle, and lung. A population pharmacokinetic study found that subject gender and weight explained ~33% of the variance in the apparent volume of distribution of methadone. Methadone is found to be secreted in saliva, sweat, breast milk, amniotic fluid and umbilical cord plasma. The concentration in cord blood is about half the maternal levels.

来源:DrugBank

吸收、分配和排泄

• 清除

由于个体间药物动力学的差异，对美沙酮清除率的估计范围在5.9-13 L/h之间，而批准的药品说明书中列出的数值在1.4到126 L/h之间。

Due to interindividual differences in pharmacokinetics, estimates of methadone's clearance have ranged from 5.9–13 L/h hours with approved monographs listing it between 1.4 to 126 L/h.

来源:DrugBank

吸收、分配和排泄

尽管美沙酮维持治疗不是哺乳的禁忌症，但最好在剂量后3-4小时，即乳汁中美沙酮水平达到峰值时避免哺乳。曾有一例报告，一名营养不良的5周大婴儿的母亲正在接受美沙酮维持治疗，婴儿在尸检中被检测出美沙酮，但药物在婴儿死亡中扮演了什么角色尚不清楚。

/MILK/ Although methadone maintenance is not a contraindication to breast feeding, it is best to avoid breast feeding 3-4 hr after the dose when peak milk levels occur. One death has been reported in a malnourished 5 week old infant whose mother was on methadone maintenance. Methadone was detected in the infant on autopsy, but it is unclear what part the drug played in the infant's death.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  美沙酮 在 bromocamphor salt 作用下， 以 乙醇 、 水 为溶剂， 以43.08 g的产率得到左美沙酮
  参考文献：
  名称：

  [EN] (R)-6-(DIMETHYLAMINO)-4,4-DIPHENYLHEPTAN-3-ONE
  [FR] (R)-6-(DIMÉTHYLAMINO)-4,4-DIPHÉNYLHEPTAN-3-ONE

  摘要：

  生产美沙酮及其分辨率以生产(R)-6-二甲氨基-4,4-二苯基庚酮((R)-美沙酮)的方法。这些方法首先生产前体化合物4-(二甲基氨基)-2,2-二苯基戊腈。将4-(二甲基氨基)-2,2-二苯基戊腈与乙基镁卤化物氧化，然后水解该复合物形成6-二甲氨基-4,4-二苯基庚酮。通过与溴樟脑盐反应来实现(R)-异构体的分辨。一旦分离，(R)-异构体会结晶。

  公开号：

  WO2013077720A1
• 作为产物：
  描述：

  盐酸美沙酮 在 potassium carbonate 、 盐酸美沙酮 、 美沙酮 、 乙醇 、 水 作用下， 以 水 为溶剂， 生成 美沙酮
  参考文献：
  名称：

  Quaternary ammonium immunogenic conjugates and immunoassay reagents

  摘要：

  本发明涉及新型季铵免疫原共轭物和报告试剂，可用于引发抗体和免疫测定。还披露了制备这种季铵免疫原共轭物的过程以及它们在免疫测定和引发抗体中的应用。

  公开号：

  US05492841A1
• 作为试剂：
  描述：

  盐酸美沙酮 在 potassium carbonate 、 盐酸美沙酮 、 美沙酮 、 乙醇 、 水 作用下， 以 水 为溶剂， 生成 美沙酮
  参考文献：
  名称：

  Quaternary ammonium immunogenic conjugates and immunoassay reagents

  摘要：

  本发明涉及新型季铵免疫原共轭物和报告试剂，可用于引发抗体和免疫测定。还披露了制备这种季铵免疫原共轭物的过程以及它们在免疫测定和引发抗体中的应用。

  公开号：

  US05492841A1

文献信息

• [EN] AZA PYRIDONE ANALOGS USEFUL AS MELANIN CONCENTRATING HORMONE RECEPTOR-1 ANTAGONISTS<br/>[FR] ANALOGUES D'AZAPYRIDONE UTILES COMME ANTAGONISTES DU RÉCEPTEUR 1 DE L'HORMONE CONCENTRANT LA MÉLANINE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2010104818A1

  公开（公告）日：2010-09-16

  MCHR1 antagonists are provided having the following Formula (I): A1 and A2 are independently C or N; E is C or N; Q1, Q2, and Q3 are independently C or N provided that at least one of Q1, Q2, and Q3 is N but not more than one of Q1, Q2, and Q3 is N; D1 is a bond, -CR8R9 X-, -XCR8R9-, -CHR8CHR9-, -CR10=CR10'-, -C≡C-, or 1,2-cyclopropyl; X is O, S or NR11; R1, R2, and R3 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower cycloalkyl, -CF3, -OCF3, -OR12 and -SR12; G is O, S or -NR15; D2 is lower alkyl, lower cycloalkyl, lower alkylcycloalkyl, lower cycloalkylalkyl, lower cycloalkoxyalkyl or lower alkylcycloalkoxy or when G is NR15, G and D2 together may optionally form an azetidine, pyrrolidine or piperidine ring; Z1 and Z2 are independently hydrogen, lower alkyl, lower cycloalkyl, lower alkoxy, lower cycloalkoxy, halo, -CF3, -OCONR14R14', -CN, -CONR14R14', -SOR12, -SO2R12, -NR14COR14', -NR14CO2R14', -CO2R12, NR14SO2R12 or COR12; R5, R6, and R7 are independently selected from the group consisting of hydrogen lower alkyl, lower cycloalkyl, -CF3, -SR12, lower alkoxy, lower cycloalkoxy, -CN, -CONR14R14', SOR12, SO2R12, NR14COR14', NR14CO2R12, CO2R12, NR14SO2R12 and -COR12; R8, R9, R10, R10', R11 are independently hydrogen or lower alkyl; R12 is lower alkyl or lower cycloalkyl; R14 and R14' are independently H, lower alkyl, lower cycloalkyl or R14 and R14' together with the N to which they are attached form a ring having 4 to 7 atoms; and R15 is independently selected from the group consisting of hydrogen and lower alkyl. Such compounds are useful for the treatment of MCHR1 mediated diseases, such as obesity, diabetes, IBD, depression, and anxiety.

  MCHR1拮抗剂具有以下化学式（I）：A1和A2独立地为C或N；E为C或N；Q1、Q2和Q3独立地为C或N，但至少其中一个为N，但不超过一个为N；D1为键，-CR8R9 X-，-XCR8R9-，-CHR8CHR9-，-CR10=CR10'-，-C≡C-，或1,2-环丙基；X为O、S或NR11；R1、R2和R3独立地从氢、卤素、低烷基、低环烷基、-CF3、-OCF3、-OR12和-SR12组成的群体中选择；G为O、S或-NR15；D2为低烷基、低环烷基、低烷基环烷基、低环烷基烷基、低环烷氧基烷基或低烷基环烷氧基，或当G为NR15时，G和D2一起可以选择形成氮杂环丙烷、吡咯烷或哌啶环；Z1和Z2独立地为氢、低烷基、低环烷基、低烷氧基、低环烷氧基、卤素、-CF3、-OCONR14R14'、-CN、-CONR14R14'、-SOR12、-SO2R12、-NR14COR14'、-NR14CO2R14'、-CO2R12、NR14SO2R12或COR12；R5、R6和R7独立地从氢、低烷基、低环烷基、-CF3、-SR12、低烷氧基、低环烷氧基、-CN、-CONR14R14'、SOR12、SO2R12、NR14COR14'、NR14CO2R12、CO2R12、NR14SO2R12和-COR12组成的群体中选择；R8、R9、R10、R10'、R11独立地为氢或低烷基；R12为低烷基或低环烷基；R14和R14'独立地为H、低烷基、低环烷基或R14和R14'与其连接的N一起形成具有4至7个原子的环；R15独立地从氢和低烷基组成的群体中选择。这些化合物对于治疗MCHR1介导的疾病，如肥胖症、糖尿病、炎症性肠病、抑郁症和焦虑症非常有用。
• [EN] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
  申请人：GALLEON PHARMACEUTICALS INC

  公开号：WO2009151744A1

  公开（公告）日：2009-12-17

  The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.

  本发明涉及基于巯基和S-亚硝基巯基的SNO化合物及其衍生物，以及它们在治疗正常呼吸控制缺失方面的用途，包括治疗与睡眠、肥胖、某些药物和其他医疗状况相关的呼吸暂停和低通气。
• [EN] NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS<br/>[FR] NOUVEAUX COMPOSÉS ET COMPOSITIONS PHARMACEUTIQUES LES COMPRENANT POUR LE TRAITEMENT DE TROUBLES INFLAMMATOIRES
  申请人：GALAPAGOS NV

  公开号：WO2017012647A1

  公开（公告）日：2017-01-26

  The present invention discloses compounds according to Formula (I), wherein R1, R3, R4, R5, L1, and Cy are as defined herein. The present invention also provides compounds, methods for the production of said compounds of the invention, pharmaceutical compositions comprising the same and their use in allergic or inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 and/or interferons. The present invention also methods for the prevention and/or treatment of the aforementioned diseases by administering a compound of the invention.

  本发明公开了根据式（I）的化合物，其中R1、R3、R4、R5、L1和Cy如本文所定义。本发明还提供了该发明的化合物、制备该化合物的方法、包括相同化合物的药物组合物以及它们在过敏或炎症症状、自身免疫疾病、增殖性疾病、移植排斥、涉及软骨周转障碍的疾病、先天软骨畸形和/或与IL6和/或干扰素过度分泌相关的疾病中的使用。本发明还提供了通过给予该发明的化合物来预防和/或治疗上述疾病的方法。
• [EN] IMIDAZOLIUM REAGENT FOR MASS SPECTROMETRY<br/>[FR] RÉACTIF D'IMIDAZOLIUM POUR SPECTROMÉTRIE DE MASSE
  申请人：HOFFMANN LA ROCHE

  公开号：WO2021234004A1

  公开（公告）日：2021-11-25

  The present invention relates to compounds which are suitable to be used in mass spectrometry as well as methods of mass spectrometric determination of analyte molecules using said compounds.

  本发明涉及适用于质谱的化合物，以及利用该化合物进行分析物分子的质谱测定方法。
• [EN] NAPHTHALENE CARBOXAMIDE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] COMPOSÉS DE NAPHTHALÈNE CARBOXAMIDE, MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1
  申请人：MERCK SHARP & DOHME

  公开号：WO2011149801A1

  公开（公告）日：2011-12-01

  The present invention is directed to naphthalene carboxamide compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimers disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

  本发明涉及式(I)的萘甲酰胺化合物，它们是M1受体阳性变构调节剂，可用于治疗M1受体参与的疾病，如阿尔茨海默病、精神分裂症、疼痛或睡眠障碍。该发明还涉及包含这些化合物的药物组合物，以及在治疗由M1受体介导的疾病中使用这些化合物和组合物。

表征谱图