97% of the dose is metabolized mostly via conjugation with glucuronic acid to produce glucuronides. Tapentadol is also metabolized into N-desmethyl tapentadol (13%) by CYP2C9 and CYP 2C19. CYP2D6 is involved in the formation of the metabolite, hydroxy tapentadol (2%). All metabolites are inactive.
来源:DrugBank
代谢
Tapentadol是一种新型的中枢作用镇痛药，它将μ-阿片受体（MOR）激动作用和去甲肾上腺素（NA）再摄取抑制结合在一个分子中。许多经典阿片类药物形成活性代谢物，这些代谢物有助于镇痛和/或副作用，涉及的细胞色素P450酶复合物可能导致药代动力学药物-药物相互作用以及由于酶多态性导致的药物疗效差异。在这里，我们报告了Tapentadol代谢物的相关性。包括主要代谢物Tapentadol-O-葡萄糖苷酸在内的9种代谢物在小鼠尾巴甩动测试中都没有镇痛效果。在小鼠苯基醌扭动测试中，只有5种代谢物显示出镇痛效果。镇痛的缺失或存在与NA转运体或MOR的中等活性（0.5 uM < K(i) < 1.1 uM）相关。然而，在人服用治疗性口服剂量Tapentadol后发现的这些代谢物的系统暴露量远低于它们在这些结合位点的相应K(i)值（超过45倍）。因此，Tapentadol形成对镇痛活性有显著贡献的代谢物的可能性非常小。
Tapentadol is a novel, centrally acting analgesic combining mu-opioid receptor (MOR) agonism and noradrenaline (NA) reuptake inhibition in a single molecule. Many classic opioids form active metabolites that contribute to analgesia and/or side effects, and the involved cytochrome P450 enzyme complex can give rise to pharmacokinetic drug-drug interactions and variability in drug efficacy due to enzyme polymorphisms. Here we report on the relevance of tapentadol metabolites. Nine metabolites, including the major metabolite tapentadol-O-glucuronide, had no analgesic effects in the tail-flick test in mice. In the phenylquinone writhing test in mice, only 5 of these metabolites showed analgesic effects. The absence or presence of analgesia correlated with moderate activity (0.5 uM < K(i) < 1.1 uM) at the NA transporter or MOR. However, the systemic exposure for these metabolites found in humans after therapeutic oral doses of tapentadol was far below their respective K(i) values at these binding sites (by a factor of > 45). Thus, it is highly unlikely that tapentadol forms metabolites that contribute in any relevant degree to its analgesic activity.
In humans, about 97% of the parent compound is metabolized. Tapentadol is mainly metabolized via Phase 2 pathways, and only a small amount is metabolized by Phase 1 oxidative pathways. The major pathway of tapentadol metabolism is conjugation with glucuronic acid to produce glucuronides. After oral administration approximately 70% (55% O-glucuronide and 15% sulfate of tapentadol) of the dose is excreted in urine in the conjugated form. A total of 3% of drug was excreted in urine as unchanged drug. Tapentadol is additionally metabolized to N-desmethyl tapentadol (13%) by CYP2C9 and CYP2C19 and to hydroxy tapentadol (2%) by CYP2D6, which are further metabolized by conjugation. Therefore, drug metabolism mediated by cytochrome P450 system is of less importance than phase 2 conjugation. None of the metabolites contribute to the analgesic activity. Tapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys.
IDENTIFICATION AND USE: Tapentadol is a Schedule II Controlled Substance that is indicated for the relief of moderate to severe acute pain (under the drug name Nucynta). HUMAN EXPOSURE AND TOXICITY: Serious, life-threatening, or fatal respiratory depression may occur with use of Nucynta ER. Potentially serious, sometimes fatal serotonin syndrome may occur with the use of tapentadol. Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea). The co-ingestion of alcohol with Nucynta ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol. Accidental ingestion of even one dose of Nucynta ER, especially by children, can result in a fatal overdose of tapentadol. Prolonged use of Nucynta ER during pregnancy can result in neonatal opioid withdrawal syndrome. ANIMAL STUDIES: In a study of pre- and postnatal development in rats, tapentadol was administered orally to pregnant and lactating rats during the late gestation and early postnatal period (resulting in up to 2.28 times the plasma exposure at the Maximum Recommended Human Dose (MRHD) on an AUC basis). Treatment-related developmental delay was observed, including incomplete ossification, and significant reductions in pup body weights and body weight gains at doses associated with maternal toxicity. At maternal tapentadol doses > or = 150 mg/kg/day, a dose-related increase in pup mortality was observed to postnatal Day 4. Tapentadol HCl was evaluated for teratogenic effects in pregnant rats and rabbits following intravenous and subcutaneous exposure during the period of embryofetal organogenesis. Evidence of embryofetal toxicity in rats included transient delays in skeletal maturation (i.e., reduced ossification) at the 40 mg/kg/day dose which was associated with significant maternal toxicity. Administration of tapentadol HCl in rabbits revealed embryofetal toxicity at doses > or =10 mg/kg/day. Findings included reduced fetal viability, skeletal delays and other variations. In addition, there were multiple malformations including gastroschisis/thoracogastroschisis, amelia/phocomelia, and cleft palate at doses > or = 10 mg/kg/day and above, and ablepharia, encephalopathy, and spina bifida at the high dose of 24 mg/kg/day. Tapentadol did not induce gene mutations in bacteria, but was clastogenic with metabolic activation in a chromosomal aberration test in V79 cells. The test was repeated and was negative in the presence and absence of metabolic activation. The one positive result for tapentadol was not confirmed in vivo in rats, using the two endpoints of chromosomal aberration and unscheduled DNA synthesis, when tested up to the maximum tolerated dose. In mice, tapentadol HCl was administered by oral gavage for 2 years. Exposure based on dose adjusted for body surface area (based on a 500 mg dose of Nucynta Extended-Release to a 50 kg human) was approximately 1.6x higher in mice than the maximum recommended human daily dose. No increase in tumor incidence was observed at any dose level.
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
Tapentadol and its metabolites are excreted almost exclusively (99%) via the kidneys. Approximately 70% (55% O-glucuronide and 15% sulfate of tapentadol) is excreted in conjugated form. A total of 3% of drug was excreted in urine as unchanged drug.
来源:DrugBank
吸收、分配和排泄
分布容积
静脉给药后，分布容积为540 ± 98升。
Following IV administration, volume of distribution is 540 ± 98 L.
Following oral administration, approximately 70% of a dose is excreted in urine as glucuronide or sulfate conjugates and only 3% is excreted unchanged. Tapentadol and its inactive metabolites are eliminated primarily by the kidneys (99%).
[EN] SALTS OR CO-CRYSTALS OF 3-(3-DIMETHYLAMINO-1-ETHYL-2-METHYL-PROPYL)-PHENOL [FR] SELS OU CO-CRISTAUX DE 3-(3-DIMETHYLAMINO-1-ETHYL-2-METHYL-PROPYL)- PHÉNOL
[EN] COMBINATIONS OF INHIBITORS OF IRAK4 WITH INHIBITORS OF BTK<br/>[FR] COMBINAISONS D'INHIBITEURS DE L'IRAK4 À L'AIDE D'INHIBITEURS DE LA BTK
申请人：BAYER PHARMA AG
公开号：WO2016174183A1
公开（公告）日：2016-11-03
The present application relates to novel combinations of at least two components, component A and component B: · component A is an IRAK4-inhibiting compound of the formula (I) as defined herein, or a diastereomer, an enantiomer, a metabolite, a salt, a solvate or a solvate of a salt thereof; · component B is a BTK-inhibiting compound, or a pharmaceutically acceptable salt thereof; and, optionally, · one or more components C which are pharmaceutical products; in which one or two of the above-defined compounds A and B are optionally present in pharmaceutical formulations ready for simultaneous, separate or sequential administration, for treatment and/or prophylaxis of diseases, and to the use thereof for production of medicaments for treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of endometriosis, lymphoma, macular degeneration, COPD, neoplastic disorders and psoriasis.
[EN] THERAPEUTIC ACRYLATES AS ENHANCED MEDICAL ADHESIVES<br/>[FR] ACRYLATES THÉRAPEUTIQUES UTILES EN TANT QU'ADHÉSIFS MÉDICAUX AMÉLIORÉS
申请人：UNIV CARNEGIE MELLON
公开号：WO2018052936A1
公开（公告）日：2018-03-22
Provided herein are therapeutic acrylate compounds useful as medical adhesives, comprising a therapeutic agent covalently linked to a methacrylate or cyanoacrylate moiety. Adhesive compositions and kits, such as liquid sutures and bone cement also are provided along with uses for the compositions.
Provided are novel prodrugs of treprostinil, as well as methods of making and methods of using these prodrugs.
提供了特瑞普罗斯汀的新型前药，以及制备这些前药的方法和使用这些前药的方法。
[EN] TARGETED RADIOPHARMACEUTICALS FOR THE DIAGNOSIS AND TREATMENT OF PROSTATE CANCER<br/>[FR] PRODUITS RADIOPHARMACEUTIQUES CIBLÉS POUR LE DIAGNOSTIC ET LE TRAITEMENT DU CANCER DE LA PROSTATE
申请人：BAYER AS
公开号：WO2021013978A1
公开（公告）日：2021-01-28
A compound of general formula (I): wherein: n is 1, 2 or 3; R1, R2, R3 and R4, independently represent OH or Q; and 20 Q represents a tissue-targeting moeity selected from the group consisting of or a stereoisomer, a hydrate, a solvate, or a salt thereof, or a mixture of same, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said 25 compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of soft tissue diseases, as a sole agent or in combination with other active ingredients.
