(+)-曲马多 | 123154-38-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 中文名称: (+)-曲马多
• 英文名称: (R,R)-tramadol
• 英文别名: (+)-Tramadol；TRAMADOL；trans-(+)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-1-cyclohexanol；(1R,2R)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol；(+)‐(1R,2R)‐tramadol；(+)-(1R,2R)-tramadol；(1R,2R)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexan-1-ol
• CAS: 123154-38-1；27203-92-5
• 化学式: C₁₆H₂₅NO₂
• 分子量: 263.38
• InChiKey: TVYLLZQTGLZFBW-ZBFHGGJFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  32.7
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

曲马多在肝脏经历广泛的首过代谢，包括N-和O-去甲基化和结合。从广泛的代谢中，已经鉴定出至少23种代谢物。有两个主要的代谢途径：曲马多的O-去甲基化产生O-去甲基曲马多（M1），由CYP2D6催化，以及N-去甲基化产生N-去甲基曲马多（M2），由CYP3A4和CYP2B6催化。患者之间药代动力学性质的广泛差异，部分可以归因于CYP2D6基因的多态性，这决定了其酶活性。CYP2D6*1被认为是与正常酶活性和“广泛代谢者”表型相关的野生型等位基因；90-95%的高加索人被认为是“广泛代谢者”（具有正常的CYP2D6功能），而剩下的5-10%被认为是“弱代谢者”，具有减少或无功能的酶。与无功能酶相关的CYP2D6等位基因包括*3、*4、*5和*6，而与降低活性相关的等位基因包括*9、*10、*17和*41。弱代谢者的CYP2D6酶活性降低，因此产生曲马多代谢物M1和M2的量减少，这最终导致镇痛效果降低，因为曲马多主要通过M1与μ-阿片受体相互作用。 这些等位基因在不同种族之间的频率也有很大差异：*3、*4、*5、*6和*41在高加索人中较为常见，而*17在非洲人中更为常见。与5-10%的高加索人相比，只有大约1%的亚洲人被认为是弱代谢者，然而亚洲人群中携带CYP2D6*10等位基因的频率要高得多（51%），这在高加索人群中相对罕见，导致曲马多的暴露量增加。 一些个体被认为是“超快速代谢者”，例如那些携带CYP2D6基因重复（CYP2D6*DUP）或倍增的个体。这些个体由于活性代谢物（M1）浓度较高，存在曲马多中毒或效果夸张的风险。这种表型的发生在大约1%至2%的东亚人（中国、日本、韩国）、1%至10%的高加索人、3%至4%的非裔美国人中可见，在某些种族/民族群体中可能超过10%（例如，大洋洲人、北非人、中东人、阿什肯纳兹犹太人、波多黎各人）。美国食品药品监督管理局（FDA）标签建议避免在这些个体中使用曲马多。

Tramadol undergoes extensive first-pass metabolism in the liver by N- and O- demethylation and conjugation. From the extensive metabolism, there have been identified at least 23 metabolites. There are two main metabolic pathways: the O-demethylation of tramadol to produce O-desmethyl-tramadol (M1) catalyzed by CYP2D6 and the N-demethylation to N-desmethyl-tramadol (M2) catalyzed by CYP3A4 and CYP2B6. The wide variability in the pharmacokinetic properties between patients can partly be ascribed to polymorphisms within the gene for CYP2D6 that determine its enzymatic activity. CYP2D6\*1 is considered the wild-type allele associated with normal enzyme activity and the "extensive metabolizer" phenotype; 90-95% of Caucasians are considered "extensive metabolizers" (with normal CYP2D6 function) while the remaining 5-10% are considered "poor metabolizers" with reduced or non-functioning enzyme. CYP2D6 alleles associated with non-functioning enzyme include *3, *4, *5, and *6 while alleles associated with reduced activity include *9, *10, *17, and *41. Poor metabolizers have reduced activity of the CYP2D6 enzyme and therefore less production of tramadol metabolites M1 and M2, which ultimately results in a reduced analgesic effect as tramadol interacts with the μ-opioid receptor primarily via M1. There are also large differences in the frequency of these alleles between different ethnicities: \*3, \*4, \*5, \*6, and \*41 are more common among Caucasians while \*17 is more common in Africans for example. Compared to 5-10% of Caucasians, only ~1% of Asians are considered poor metabolizers, however Asian populations carry a much higher frequency (51%) of the CYP2D6\*10 allele, which is relatively rare in Caucasian populations and results in higher exposure to tramadol. Some individuals are considered "ultra-rapid metabolizers", such as those carrying CYP2D6 gene duplications (CYP2D6*DUP) or multiplications. These individuals are at risk of intoxication or exaggerated effects of tramadol due to higher concentrations of its active metabolite (M1). The occurrence of this phenotype is seen in approximately 1% to 2% of East Asians (Chinese, Japanese, Korean), 1% to 10% of Caucasians, 3% to 4% of African-Americans, and may be >10% in certain racial/ethnic groups (ie, Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). The FDA label recommends avoiding the use of tramadol in these individuals.

来源:DrugBank

代谢

盐酸曲马多口服给药后，通过多种途径广泛代谢，包括CYP2D6和CYP3A4，以及通过母体和代谢物的结合。大约30%的剂量以未改变药物的形态从尿液中排出，而60%的剂量以代谢物的形式排出。其余部分以未识别的或不可提取的代谢物形式排出。主要的代谢途径似乎是肝脏中的N-和O-去甲基化以及葡萄糖苷酸化或硫酸化。一种代谢物（O-去甲基曲马多，记为M1）在动物模型中具有药理活性。M1的形成依赖于CYP2D6，因此会受到抑制，这可能影响治疗效果。

Tramadol is extensively metabolized after oral administration by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. The major metabolic pathways appear to be N- and O-demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyltramadol, denoted M1) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response

来源:Hazardous Substances Data Bank (HSDB)

代谢

曲马多有多达11种代谢物。其中一种代谢物（O-去甲基曲马多，也称为M1）可能比原药具有更强的阿片样效果（例如，比曲马多强200-300倍的阿片样效果），但仍然低于吗啡。在能够产生足够量这种代谢物的动物中，部分镇痛作用可能归因于活性代谢物介导的阿片样效果。其他代谢物尚未显示出具有活性的镇痛作用。

Tramadol has as many as 11 metabolites. One metabolite (o-desmethyl tramadol, also called M1) may have greater opiate effects than the parent drug (for example, 200-300 times greater opiate effect than tramadol) but still lower than morphine. In animals that produce this metabolite in sufficient amounts, some analgesic action may be attributed to opiate-mediated effects from the active metabolite. The other metabolites have not been shown to have active analgesic activity.

来源:Hazardous Substances Data Bank (HSDB)

代谢

曲马多通过多种途径广泛代谢，包括CYP2D6和CYP3A4，以及通过母体代谢物的结合。其中一种代谢物，M1，在动物模型中具有药理学活性。M1的形成依赖于细胞色素P-450(2D6)，因此可能会受到代谢诱导和抑制的影响，这可能会影响治疗效果。/未指定盐类/

Tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent metabolites. One metabolite, M1, is pharmacology active in animal models. The formation of M1 is dependent upon Cytochrome P-450(2D6) and as such is subject to both metabolic induction and inhibition which may affect the therapeutic response. /Salt not specified/

来源:Hazardous Substances Data Bank (HSDB)

代谢

盐酸曲马多是一种合成阿片类药物，广泛用于术后和慢性疼痛的治疗。仅因盐酸曲马多导致的致命过量并不常见；更常见的是盐酸曲马多与其他物质联合使用导致的中毒。本文报告了一名48岁女性因盐酸曲马多中毒自杀的案例。通过气相色谱/质谱法(GC/MS)在生物流体（股动脉血、胆汁、尿液、胃内容物）和内脏（大脑、肺、肝脏和肾脏）中检测到了盐酸曲马多及其代谢物O-去甲基曲马多（M1）、N-去甲基曲马多（M2）、N,N-去甲基曲马多（M3）、N,O-去甲基曲马多（M5）。股动脉血中的盐酸曲马多浓度为61.83微克/毫升，大约是认为致命浓度的30倍。与其他作者的研究一致，M1的形成优先于M2（M1/M2比值>1）表明是急性死亡，而M1/M2比值<1则表明死亡是在摄入后较长时间发生的。

Tramadol is a synthetic opioid, widely used for post-surgical and chronic pain. Lethal overdose due only to tramadol is not common; more often the poisoning is due to tramadol in combination with other substances. Reported is a suicidal case of lethal tramadol poisoning in a 48-year-old woman. Tramadol and its metabolites O-desmethyltramadol (M1), N-desmethyltramadol (M2), N,N-didesmethyltramadol (M3), N,O-didesmethyltramadol (M5) were detected by GC/MS in biological fluids (femoral blood, bile, urine, gastric content) and viscera (brain, lung, liver and kidney). The tramadol concentration in femoral blood was 61.83 ug/mL which is approximately 30 times higher than that believed to be lethal. According with other Authors, a preferential formation of M1 over M2 (M1/M2 ratio >1) is indicative of acute death, while M1/M2 ratio <1 suggests that death occurred after a longer time lapse from ingestion.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

识别和使用：曲马多是一种白色、无味、具有苦味的结晶性粉末。曲马多是一种阿片类镇痛药，用于成人中至中重度疼痛的管理。在兽医护理中，它可用于治疗手术后或慢性疼痛或咳嗽。人类暴露和毒性：过量的表现与其他阿片类药物激动剂相似，包括呼吸抑制、嗜睡、骨骼肌松弛、昏迷、癫痫、心动过缓、低血压、心脏骤停、瞳孔缩小、呕吐、皮肤冷湿、心脏衰竭和死亡。已报告严重的和罕见致命的过敏性反应。其他报告的过敏反应包括瘙痒、荨麻疹、血管神经性水肿、支气管痉挛、中毒性表皮坏死松解症和史蒂文斯-约翰逊综合征。曲马多可能会发生潜在的致命性血清素综合征，尤其是在同时使用其他血清素能药物、影响血清素代谢的药物（例如，单胺氧化酶抑制剂）或影响曲马多代谢的药物（例如，细胞色素P-450 [CYP]同工酶2D6和3A4的抑制剂）时。曲马多的使用与低钠血症风险增加有关，需要住院治疗。一项研究表明，曲马多对胎儿的致畸作用有适度增加的风险。在怀孕期间使用曲马多，新生儿戒断综合症的风险很大。动物研究：2009-2013年间，美国防止虐待动物协会动物毒物控制中心报告了910例单一曲马多暴露。在749只狗中，有142只出现症状。症状包括镇静/嗜睡、呕吐、心动过速、发声或共济失调和激动或颤抖。在157只猫中，有96只出现症状，如瞳孔散大、过度流涎、嗜睡、共济失调或心动过速和呕吐。5-羟色胺减少的大鼠倾向于发生曲马多诱导的癫痫，5-羟色胺浓度与癫痫阈值呈负相关。在小鼠、大鼠和兔子的母体毒性剂量下，曲马多显示出胚胎毒性和胎儿毒性，但在这些剂量水平下并未表现出致畸性。在以下实验中，曲马多没有表现出致突变性： Ames沙门氏菌微体活化实验、CHO/HPRT哺乳动物细胞实验、小鼠淋巴瘤实验（在无代谢激活的情况下）、小鼠显性致死突变实验、中国仓鼠染色体畸变实验以及小鼠和中国仓鼠骨髓微核实验。在存在代谢激活的小鼠淋巴瘤实验和 rats的微核实验中，出现了微弱的致突变结果。在26周内，以大约是成人每天400毫克/天（基于体表面积转换）的两倍口服剂量的曲马多，在小鼠中没有观察到致癌作用；在大约两年的时间内，以大约是小鼠每天400毫克/天（基于体表面积转换）的两倍口服剂量的曲马多，在大鼠中也没有观察到致癌作用。在小鼠中以高达0.36倍成人每天400毫克/天（基于体表面积转换）的口服剂量，大约两年的时间内观察到两种常见的鼠类肿瘤，肺和肝脏肿瘤有轻微但统计学显著的增加。

IDENTIFICATION AND USE: Tramadol is white, odorless crystalline powder with a bitter taste. Tramadol is an opioid analgesic which is indicated for the management of moderate to moderately severe pain in adults. In veterinary care, it may be used for the treatment of post-operative or chronic pain or cough. HUMAN EXPOSURE AND TOXICITY: Manifestations of overdosage are similar to those of other opiate agonists and include respiratory depression, lethargy, skeletal muscle flaccidity, coma, seizure, bradycardia, hypotension, cardiac arrest, miosis, vomiting, cold and clammy skin, cardiac collapse, and death. Serious and rarely fatal anaphylactoid reactions have been reported. Other reported hypersensitivity reactions include pruritus, urticaria, angioedema, bronchospasm, toxic epidermal necrolysis, and Stevens-Johnson syndrome. Potentially life-threatening serotonin syndrome may occur with tramadol, particularly with concurrent use of other serotonergic drugs, drugs that impair the metabolism of serotonin (e.g., MAO inhibitors), or drugs that impair the metabolism of tramadol (e.g., inhibitors of cytochrome P-450 [CYP] isoenzymes 2D6 and 3A4). The use of tramadol has been associated with an increased risk of hyponatremia requiring hospitalization. One study suggests a moderately increased risk of a teratogenic effect of tramadol. When tramadol is used during pregnancy, there is a serious risk for neonatal abstinence syndrome. ANIMAL STUDIES: There were 910 single agent exposures to tramadol reported to the ASPCA Animal Poison Control Center during 2009-2013. Of the 749 dogs, 142 were symptomatic. Symptoms included being sedated/lethargic, vomiting, tachycardic, vocalizing or ataxic, and agitated or tremoring. Of the 157 cats, 96 were symptomatic with symptoms such as having mydriasis, hypersalivating, lethargic, ataxic or tachycardic, and vomiting. Serotonin-reduced rats were predisposed to tramadol-induced seizures, and serotonin concentrations were negatively associated with seizure thresholds. Tramadol has been shown to be embryotoxic and fetotoxic in mice, rats, and rabbits at maternally toxic doses, but was not teratogenic at these dose levels. Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. No carcinogenic effect of tramadol was observed in mice at oral doses up to approximately twice the MDHD of 400 mg/day for a 60 kg adult based on body surface conversion, for 26 weeks and in rats at oral doses up to approximately twice the MDHD for two years. A slight, but statistically significant, increase in two common murine tumors, pulmonary and hepatic, was observed in mice dosed orally up to 0.36 times the MDHD for approximately two years.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

Tramadol及其O-去甲基代谢物（M1）是选择性、弱效的μ阿片受体激动剂。阿片受体与G蛋白偶联受体相关联，并通过激活效应蛋白的G蛋白，作为突触传递的正负调节因子。由于效应系统是位于质膜内表面的腺苷酸环化酶和cAMP，阿片类药物通过抑制腺苷酸环化酶来减少细胞内cAMP。随后，痛觉神经递质如P物质、GABA、多巴胺、乙酰胆碱和去甲肾上腺素的释放被抑制。Tramadol的镇痛特性可以归因于它在中枢神经系统中的去甲肾上腺素和5-羟色胺再摄取阻断，这抑制了脊髓中的疼痛传递。(+)-对映体对μ阿片受体的亲和力更高，优先抑制5-羟色胺再摄取并增强5-羟色胺的释放。(-)-对映体通过刺激α2-肾上腺素受体，优先抑制去甲肾上腺素的再摄取。

Tramadol and its O-desmethyl metabolite (M1) are selective, weak OP3-receptor agonists. Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. The analgesic properties of Tramadol can be attributed to norepinephrine and serotonin reuptake blockade in the CNS, which inhibits pain transmission in the spinal cord. The (+) enantiomer has higher affinity for the OP3 receptor and preferentially inhibits serotonin uptake and enhances serotonin release. The (-) enantiomer preferentially inhibits norepinephrine reuptake by stimulating alpha(2)-adrenergic receptors.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 肝毒性

血清转氨酶水平在接受曲马多的患者中可能会升高，尤其是在高剂量时。故意和意外过量使用曲马多可能导致呼吸暂停以及急性肝衰竭，已经报道了若干致命的案例。然而，在这些案例中，肝脏损伤可能是由呼吸暂停引起的休克、缺氧或缺血所致。曲马多过量导致的肝脏损伤还与高氨血症、乳酸酸中毒和肝脏脂肪变性有关，这表明直接的线粒体损伤。在某些情况下，曲马多过量后的急性肝衰竭可能与单独或与曲马多联合使用的对乙酰氨基酚有关。临床上明显的推荐剂量曲马多特异质肝损伤尚未有报道。

Serum aminotransferase levels can be elevated in a small proportion of patients receiving tramadol, particularly with high doses. Intentional and accidental overdoses of tramadol can cause respiratory arrest as well as acute liver failure, several fatal instances of which have been reported. In these cases, however, the liver injury may have been caused by shock, hypoxia or ischemia secondary to the respiratory arrest. Liver injury attributed to tramadol overdose has also been associated with hyperammonemia, lactic acidosis and hepatic steatosis, suggestive of direct mitochondrial injury. In some situations, acute liver failure after tramadol overdose may be related to acetaminophen taken separately or in combination with tramadol. Clinically apparent idiosyncratic liver injury with recommended doses of tramadol has not been reported.

来源:LiverTox

毒理性

• 药物性肝损伤

化合物：曲马多

Compound:tramadol

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：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

口服给药：曲马多以其消旋混合物形式给药，循环中可以检测到曲马多和其主要代谢物M1的[-]和[+]形式。给药后，消旋曲马多迅速且几乎完全被吸收，生物利用度为75%。这种吸收和生物利用度的差异可以归因于20-30%的首过代谢。曲马多及其主要代谢物M1的血浆峰浓度分别在大约2小时和3小时出现。单次口服100mg曲马多后，Cmax大约为300μg/L，Tmax为1.6-1.9小时，而代谢物M1的Cmax为55μg/L，Tmax为3小时。曲马多和M1的稳态血浆浓度在给药两天内达到。没有自我诱导的证据。多次口服给药后，Cmax比单次给药高16%，AUC高36%，这表明可饱和的首过肝代谢在提高生物利用度方面可能发挥作用。 肌内给药：曲马多在肌内给药后迅速且几乎完全吸收。注射50mg曲马多后，Cmax为166μg/L，Tmax为0.75小时。 直肠给药：使用含100mg曲马多的栓剂进行直肠给药后，Cmax为294μg/L，Tmax为3.3小时。绝对生物利用度高于口服给药（77%对75%），这可能是由于直肠给药与口服给药相比首过代谢减少。

**Oral Administration** Tramadol is administered as a racemate, with both the [-] and [+] forms of both tramadol and the M1 metabolite detected in circulation. Following administration, racemic tramadol is rapidly and almost completely absorbed, with a bioavailability of 75%. This difference in absorption and bioavailability can be attributed to the 20-30% first-pass metabolism. Peak plasma concentrations of tramadol and the primary metabolite M1 occur at two and three hours, respectively. Following a single oral dose of 100mg of tramadol, the Cmax was found to be approximately 300μg/L with a Tmax of 1.6-1.9 hours, while metabolite M1 was found to have a Cmax of 55μg/L with a Tmax of 3 hours. Steady-state plasma concentrations of both tramadol and M1 are achieved within two days of dosing. There is no evidence of self-induction. Following multiple oral doses, Cmax is 16% higher and AUC is 36% higher than after a single dose, demonstrating a potential role of saturable first-pass hepatic metabolism in increasing bioavailability. **Intramuscular Administration** Tramadol is rapidly and almost completely absorbed following intramuscular administration. Following injection of 50mg of tramadol, Cmax of 166μg/L was found with a Tmax of 0.75 hours. **Rectal Administration** Following rectal administration with suppositories containing 100mg of tramadol, Cmax of 294μg/L was found with a Tmax of 3.3 hours. The absolute bioavailability was found to be higher than oral administration (77% vs 75%), likely due to reduced first-pass metabolism with rectal administration compared to oral administration.

来源:DrugBank

吸收、分配和排泄

• 消除途径

曲马多主要通过肝脏代谢消除，其代谢物主要通过肾脏排泄，占排泄总量的90%，剩余的10%通过粪便排泄。大约30%的剂量以原药形式在尿液中排出，而60%的剂量以代谢物形式排出。消旋曲马多和消旋M1的平均终末血浆消除半衰期分别为6.3 ± 1.4小时和7.4 ± 1.4小时。消旋曲马多在多次给药后，其血浆消除半衰期从大约六小时增加到七小时。

Tramadol is eliminated primarily through metabolism by the liver and the metabolites are excreted primarily by the kidneys, accounting for 90% of the excretion while the remaining 10% is excreted through feces. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing.

来源:DrugBank

吸收、分配和排泄

• 分布容积

度冷丁的分布容积据报道在2.6-2.9 L/kg的范围内。度冷丁具有很高的组织亲和力；口服给药后的总分布容积为306L，而静脉给药后为203L。度冷丁能够穿过血脑屏障，口服给药后10分钟达到脑内峰值浓度。它也能穿过胎盘屏障，脐带血中的浓度约为母体浓度的80%。

The volume of distribution of tramadol is reported to be in the range of 2.6-2.9 L/kg. Tramadol has high tissue affinity; the total volume of distribution after oral administration was 306L and 203L after parenteral administration. Tramadol crosses the blood-brain barrier with peak brain concentrations occurring 10 minutes following oral administration. It also crosses the placental barrier with umbilical concentrations being found to be ~80% of maternal concentrations.

来源:DrugBank

吸收、分配和排泄

• 清除

在临床试验中，曲马多的清除率在肾功能受损的患者中为3.73毫升/分钟/千克，在健康成人中为8.50毫升/分钟/千克。

In clinical trials, the clearance rate of tramadol ranged from 3.73 ml/min/kg in renal impairment patients to 8.50 ml/min/kg in healthy adults.

来源:DrugBank

吸收、分配和排泄

这项研究的目标是确定两种口服剂量的曲马多（5毫克/千克和10毫克/千克）及其主要代谢物（O-去甲基曲马多）（M1）在红海龟（Caretta caretta）中的药代动力学。口服给药后，5毫克/千克和10毫克/千克剂量的曲马多的半衰期分别为20.35小时和22.67小时，而M1的半衰期分别为10.23小时和11.26小时。口服给药5毫克/千克和10毫克/千克的曲马多后，其最大浓度（Cmax）分别为373和719纳克/毫升，而M1的分别为655和1,376纳克/毫升。两种剂量下的曲马多口服给药在红海龟中均提供了可测量的曲马多和O-去甲基曲马多血浆浓度，持续数天且没有不良反应。当曲马多以10毫克/千克的剂量给药时，曲马多和O-去甲基曲马多的血浆浓度至少在48小时和72小时内保持在100纳克/毫升以上。

The objective of this study was to determine the pharmacokinetics of two orally administered doses of tramadol (5 and 10 mg/kg) and its major metabolite (O-desmethyltramadol) (M1) in loggerhead sea turtles (Caretta caretta). After oral administration, the half-life of tramadol administered at 5 and 10 mg/kg was 20.35 and 22.67 hr, whereas the half-life of M1 was 10.23 and 11.26 hr, respectively. The maximum concentration (Cmax) for tramadol after oral administration at 5 mg/kg and 10 mg/kg was 373 and 719 ng/mL, whereas that of M1 was 655 and 1,376 ng/mL, respectively. Tramadol administered orally to loggerhead sea turtles at both dosages provided measurable plasma concentrations of tramadol and O-desmethyltramadol for several days with no adverse effects. Plasma concentrations of tramadol and O-desmethyltramadol remained >/= 100 ng/mL for at least 48 and 72 hr when tramadol was administered at 10 mg/kg.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  (+)-曲马多 在 sodium anthraquinone-2-sulfonate 、 氧气 、 三氟乙酸 、 sodium bromide 作用下， 以 水 、 乙腈 为溶剂， 反应 4.0h， 以74%的产率得到(1R,2R)-1-(4-bromo-3-methoxyphenyl)-2-((dimethylamino)methyl)cyclohexan-1-ol
  参考文献：
  名称：

  蒽醌对富电子芳烃和杂芳烃的光催化氧化溴化反应

  摘要：

  通过布朗斯台德酸的质子化，蒽醌-2-磺酸钠（SAS）的估计激发氧化电势相对于SCE从1.8 V增加到约2.3V。质子化蒽醌提高的光氧化能力可用于富电子（杂）芳烃和药物的区域选择性氧化溴化，收率很好。温和的反应条件与许多官能团兼容，例如双键和三键，酮，酰胺和胺，羟基，羧酸和氨基甲酸酯。机理研究表明，芳烃的光氧化反应继之以亲核性溴化物添加是可能的途径。

  DOI：

  10.1002/adsc.201701276
• 作为产物：
  描述：

  (1R,2R)-2-(dimethylaminomethyl)-1-(3-methoxyphenyl)-cyclohexanol di-p-toluoyl-D-tartaric acid salt 在 sodium carbonate 作用下， 以 水 为溶剂， 生成 (+)-曲马多
  参考文献：
  名称：

  SUBSTITUTED CYCLOHEXANOLS

  摘要：

  本文披露了Formula I或Formula II的替代环己醇类阿片受体调节剂和/或神经递质再摄取调节剂，其制备方法，药物组合物以及使用方法。

  公开号：

  US20090028873A1

文献信息

• [EN] DIHYDROPYRROLONAPHTYRIDINONE COMPOUNDS AS INHIBITORS OF JAK<br/>[FR] COMPOSÉS DE DIHYDROPYRROLONAPHTYRIDINONE COMME INHIBITEURS DE JAK
  申请人：TAKEDA PHARMACEUTICAL

  公开号：WO2010144486A1

  公开（公告）日：2010-12-16

  Disclosed are JAK inhibitors of formula (I) where G1, R1, R2, R3, R4, R5, R6, and R7 are defined in the specification. Also disclosed are pharmaceutical compositions, kits and articles of manufacture which contain the compounds, methods and materials for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other diseases, disorders or conditions associated with JAK.

  揭示了式(I)的JAK抑制剂，其中G1、R1、R2、R3、R4、R5、R6和R7在规范中定义。还披露了含有这些化合物的药物组合物、试剂盒和制造物品，制备这些化合物的方法和材料，以及使用这些化合物治疗涉及免疫系统和炎症的疾病、紊乱和症状的方法，包括类风湿关节炎、血液恶性肿瘤、上皮癌（即癌症）和其他与JAK相关的疾病、紊乱或症状。
• [EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
  申请人：ASTRAZENECA AB

  公开号：WO2016055858A1

  公开（公告）日：2016-04-14

  The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.

  本申请涉及式(I)、(Ia)或(Ib)的化合物及其药物组合物/制剂。本申请进一步涉及治疗或预防与Αβ相关的病理学，如唐氏综合症，β-淀粉样蛋白血管病，如但不限于脑淀粉样蛋白血管病或遗传性脑出血，与认知损害相关的疾病，如但不限于MCI（“轻度认知损害”），阿尔茨海默病，记忆丧失，与阿尔茨海默病相关的注意力缺陷症状，与疾病如阿尔茨海默病或痴呆症相关的神经退行性疾病，包括混合性血管性和退行性起源的痴呆，早老性痴呆，老年性痴呆和与帕金森病相关的痴呆的方法。
• [EN] CROSS-LINKED PYRROLOBENZODIAZEPINE DIMER (PBD) DERIVATIVE AND ITS CONJUGATES<br/>[FR] DÉRIVÉ DE DIMÈRE DE PYRROLOBENZODIAZÉPINE RÉTICULÉ (PBD) ET SES CONJUGUÉS
  申请人：HANGZHOU DAC BIOTECH CO LTD

  公开号：WO2020006722A1

  公开（公告）日：2020-01-09

  A novel cross-linked cytotoxic agents, pyrrolobenzo-diazepine dimer (PBD) derivatives, and their conjugates to a cell-binding molecule, a method for preparation of the conjugates and the therapeutic use of the conjugates.

  一种新型的交联细胞毒剂，吡咯苯并二氮杂环二聚体（PBD）衍生物，以及它们与细胞结合分子的结合物，一种制备这些结合物的方法以及这些结合物的治疗用途。
• [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] QUINAZOLINE DERIVATIVES, COMPOSITIONS, AND USES RELATED THERETO<br/>[FR] DÉRIVÉS DE QUINAZOLINE, COMPOSITIONS ET UTILISATIONS ASSOCIÉES
  申请人：UNIV EMORY

  公开号：WO2013181135A1

  公开（公告）日：2013-12-05

  The disclosure relates to quinazoline derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to inhibitors of NADPH-oxidases (Nox enzymes) and/or myeloperoxidase.

  该披露涉及喹唑啉衍生物、组合物以及相关方法。在某些实施例中，该披露涉及NADPH-氧化酶（Nox酶）和/或髓过氧化物酶的抑制剂。