右旋达尔丰 | 469-62-5

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 中文名称: 右旋达尔丰
• 中文别名: 右旋丙氧芬；右丙氧芬；乙腈标准样品；达尔丰；丙氧芬;右丙氧芬；丙氧芬
• 英文名称: propoxyphene
• 英文别名: dextropropoxyphene；(+)-Propoxyphene；(1S,2R)-1-benzyl-3-(dimethylamino)-2-methyl-1-phenylpropyl propionate；d-propoxyphene；[(2S,3R)-4-(dimethylamino)-3-methyl-1,2-diphenylbutan-2-yl] propanoate
• CAS: 469-62-5
• 化学式: C₂₂H₂₉NO₂
• 分子量: 339.478
• InChiKey: XLMALTXPSGQGBX-GCJKJVERSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  25
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  3

ADMET

代谢

肝脏的

Hepatic

来源:DrugBank

代谢

异丙氧苯酚通过肠道和肝脏酶的广泛首过代谢。异丙氧苯酚主要通过N-去甲基化（由细胞色素P-450（CYP）同工酶3A4介导）形成去甲异丙氧苯酚。环羟基化和葡萄糖苷酸形成似乎是与该药物相关的次要代谢途径。去甲异丙氧苯酚的消除半衰期为30-36小时。去甲异丙氧苯酚和未改变的异丙氧苯酚主要通过尿液排出。口服65毫克剂量的盐酸异丙氧苯酚后，大约20-25%可以在48小时内以未改变的药物（微量）和自由或结合的去甲异丙氧苯酚的形式在尿液中回收。看来未改变的药物主要在6小时内排出，代谢物在给药后6至48小时内排出。异丙氧苯酚的肾清除率约为2.6升/分钟。

Propoxyphene undergoes extensive first-pass metabolism by intestinal and hepatic enzymes. Propoxyphene is metabolized mainly via N-demethylation (mediated by cytochrome P-450 (CYP) isoenzyme 3A4) to form norpropoxyphene. Ring hydroxylation and glucuronide formation appear to be minor metabolic pathways for the drug. Norpropoxyphene has an elimination half-life of 30-36 hours. Norpropoxyphene and unchanged propoxyphene are excreted mainly in urine. Approximately 20-25% of an orally administered 65-mg dose of propoxyphene hydrochloride may be recovered in urine as unchanged drug (trace amount) and free or conjugated norpropoxyphene within 48 hours.It appears that the unchanged drug is excreted mainly within 6 hours and the metabolite is excreted in the 6- to 48-hour period following administration. Renal clearance of propoxyphene is about 2.6 L/minute.

来源:Hazardous Substances Data Bank (HSDB)

代谢

原生的和苯巴比妥诱导的大鼠体内形成了细胞色素P450代谢中间体复合物，与原药丙氧吩有关。体内的形成与其在体外形成代谢中间体复合物和抑制混合功能氧化反应的能力相关。

Formation of cytochrome p450 metabolic intermediate complexes in vivo occurred with propoxyphene in native & phenobarbital-induced rats. In vivo formation correlated with relative ability for it to form metabolic intermediate complexes & inhibit mixed function oxidation reactions in vitro.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在猪中产生3-二甲氨基-1,2-二苯基-2-丁基丙酸酯-n-氧化物，在大鼠中产生3-甲基氨基-1,2-二苯基-2-丁基丙酸酯。根据表格。

Yields 3-dimethylamino-1,2-diphenyl-2-butyl propionate-n-oxide iN pig & 3-methylamino-1,2-diphenyl-2-butyl propionate iN rat. From table/

来源:Hazardous Substances Data Bank (HSDB)

代谢

系统前代谢主要被认为发生在肝脏，肠道也有一些参与。本研究的目的是调查这两个器官在代谢镇痛药d-丙氧芬方面的各自部分。将药理剂量的d-丙氧芬给予雄性Wistar大鼠的十二指肠（ID）、门静脉（IP）和股静脉（IV）。还向肝切除大鼠或胆管引流大鼠以及静脉（IV）、门静脉（IP）或十二指肠（ID）中给予（14）C-d-丙氧芬的示踪剂量。还研究了在肝脏和肠道微粒体中发生的脱甲基作用。口服给药后获得的DP绝对生物利用度是门脉给药后观察到的两倍高（分别为48.9%和23.2%），这一结果与预期存在肝脏酶饱和现象的结果相反（即生物利用度较低）。在给予（14）C-d-丙氧芬后，与门静脉单次注射或在20分钟内注射相比，IV或ID给药后（14）C-d-丙氧芬的累积排泄显著降低。标记化合物的胆汁排泄情况则相反，IV或ID给药后比IP给药后更大，这表明d-丙氧芬在肝脏的代谢受到肠外转化的影响。这很可能发生在肠道中，因为IV给药后（14）C-d-丙氧芬的产生与ID给药后相似。这种转化并没有阻止在系统血液中检测到d-丙氧芬，但足以增加随胆汁排出的部分并减少脱甲基NP的部分。脱甲基主要发生在肝脏，因为在肝切除大鼠中（14）C-d-丙氧芬的产生几乎被消除。此外，肝脏来源的微粒体能够脱甲基d-丙氧芬，而肠道来源的微粒体则不能。我们的数据表明，口服给药后肠道中发生的d-丙氧芬转化是导致药物肝代谢变化的原因。

Presystemic metabolism is believed to occur mainly in the liver with some minor intestinal participation. The aim of this study was to investigate the respective part of each of these two organs in the metabolism of the analgesic d-propoxyphene. Pharmacological doses of d-propoxyphene were given in the duodenum (ID), the portal vein (IP), and the femoral vein (IV) of male Wistar rats. A tracer dose of (14)C-d-propoxyphene was also administered either in IV, IP, or ID as well as in hepatectomized rats or rats with bile duct diversion. In vitro demethylation occurring in liver and intestinal microsomes was also studied. Absolute DP bioavailability obtained after oral administration was two times higher than that observed after portal administration (48.9% vs. 23.2%, respectively), an result opposite (i.e. a lower bioavailability) of that expected on the basis of the existence of a liver enzyme saturation phenomenon. The (14)C-d-propoxyphene cumulative excretion after (14)C-d-propoxyphene administration was significantly lower after IV or ID administration than after injection in the portal vein as a bolus or within 20 min. The biliary excretion of the labeled compound varied in the opposite direction, being greater after IV or ID than after IP administration, suggesting that the metabolism of d-propoxyphene in the liver is influenced by an extrahepatic transformation. This most likely occurs in the gut since the production of (14)C-d-propoxyphene after IV administration was similar to that after ID administration. This transformation did not prohibit d-propoxyphene detection in the systemic blood but was sufficient to increase the part eliminated with bile and to decrease the part demethylated NP. Demethylation mainly occurs in the liver since the production of (14)C-d-propoxyphene was nearly abolished in hepatectomized rats. Furthermore, microsomes of hepatic but not of intestinal origin were able to demethylate d-propoxyphene. Our data suggest that the transformation of d-propoxyphene occurring in gut after oral administration is responsible for changes in the hepatic metabolism of the drug.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 药物性肝损伤

化合物：丙氧芬

Compound:propoxyphene

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

药物性肝损伤标注：低药物性肝损伤关注

DILI Annotation:Less-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

严重程度等级：3

Severity Grade:3

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

“标签部分：不良反应”

Label Section:Adverse reactions

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 美国食品药品监督管理局批准的药物标签用于研究药物诱导的肝损伤，《药物发现今日》，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按人类发展药物诱导肝损伤风险排名的最大参考药物清单。《药物发现今日》2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

吸收、分配和排泄

• 消除途径

主要代谢途径是细胞色素CYP3A4介导的N-去甲基化生成去甲右丙氧芬，后者通过肾脏排出。在48小时内，大约20%至25%的右丙氧芬给药剂量通过尿液排出，其中大部分为自由型或结合型的去甲右丙氧芬。

The major route of metabolism is cytochrome CYP3A4 mediated N-demethylation to norpropoxyphene, which is excreted by the kidneys. In 48 hours, approximately 20% to 25% of the administered dose of propoxyphene is excreted via the urine, most of which is free or conjugated norpropoxyphene.

来源:DrugBank

吸收、分配和排泄

• 分布容积

16 升/千克

16 L/kg

来源:DrugBank

吸收、分配和排泄

• 清除

2.6升/分钟

2.6 L/min

来源:DrugBank

吸收、分配和排泄

口服给药后，盐酸丙氧吩和nap磺酸盐主要在上段小肠吸收。nap磺酸盐似乎比盐酸盐吸收得更慢。等摩尔剂量的盐酸丙氧吩或nap磺酸盐能提供相似的血浆浓度。口服65、130或195毫克盐酸丙氧吩的生物利用度分别等同于口服100、200或300毫克丙氧吩nap磺酸盐。

Following oral administration, propoxyphene hydrochloride and napsylate are absorbed principally in the upper small intestine. The napsylate salt appears to be absorbed more gradually than the hydrochloride salt. Equimolar doses of propoxyphene hydrochloride or napsylate provide similar plasma concentrations. The bioavailability of oral propoxyphene hydrochloride doses of 65, 130, or 195 mg is equivalent to that of oral propoxyphene napsylate doses of 100, 200, or 300 mg, respectively.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

服用盐酸丙氧吩胶囊或丙氧吩萘甲酸酯悬浮液（美国已不再商业销售）后，通常在2-2.5小时内达到丙氧吩血药浓度峰值，而服用丙氧吩萘甲酸酯片后，通常在3小时内达到峰值。镇痛效果在15分钟至1小时内出现，并持续4-6小时。治疗性丙氧吩血药浓度为50纳克/毫升或更高。推荐剂量的65毫克盐酸丙氧吩可能达到的峰值血药浓度范围为50-120纳克/毫升，而丙氧吩的代谢物去甲丙氧吩的浓度范围为100-200纳克/毫升。

Peak plasma propoxyphene concentrations are usually achieved within 2-2.5 hours following oral administration of propoxyphene hydrochloride capsules or propoxyphene napsylate suspension (no longer commercially available in the US) and within 3 hours following oral administration of propoxyphene napsylate tablets. The analgesic effect occurs within 15 minutes to 1 hour and persists for 4-6 hours. Therapeutic plasma propoxyphene concentrations are 50 ng/mL or greater. Peak plasma concentrations achieved with the recommended 65-mg dose of propoxyphene hydrochloride may range from 50-120 ng/mL, while concentrations of the norpropoxyphene metabolite range from 100-200 ng/mL.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  右旋达尔丰 在 盐酸 、 双氧水 、 臭氧 作用下， 以 甲醇 、 乙醇 、 乙酸乙酯 为溶剂， 生成 (2S)-2,3-diphenyl-2-hydroxypropanoic acid
  参考文献：
  名称：

  Analgesics. The Absolute Configuration of α-(+)-4-Dimethylamino-1,2-diphenyl- 3-methyl-2-propionoxybutane, d-Propoxyphene

  摘要：

  DOI：

  10.1021/jo01044a056
• 作为产物：
  描述：

  cataflam 、 盐酸右丙氧芬 以 水 为溶剂， 反应 0.53h， 生成 右旋达尔丰
  参考文献：
  名称：

  Narcotic-NSAID ion pairs

  摘要：

  本发明提供了一种离子对化合物，其化学式为[narcotic]+[A]−，其中[narcotic]+表示至少一种麻醉剂的至少一个阳离子或其一个或多个立体异构体，[A]−表示至少一种NSAID的至少一个阴离子或其一个或多个立体异构体。离子对化合物的一个例子是丙氧芬地塞米。离子对化合物或其药物组成物在治疗广泛的表明需要镇痛剂、抗炎药物或两者的情况下有用。在规定使用条件下，离子对化合物在低pH环境（如胃中）表现出差或完全不溶性，但具有良好的化学稳定性。离子对化合物在较高pH环境（如小肠中）中容易溶解和解离，以释放组成的麻醉剂和NSAID。

  公开号：

  US20050203115A1

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 manufa