DHE is metabolized in the liver to four identified metabolites. 8'-β-hydroxy dihydroergotamine is the primary metabolite and an active one with equipotency for adrenergic and 5-HT receptors. 8'-β-hydroxy dihydroergotamine is present at plasma concentrations 5-7 times that of DHE. The remaining metabolites are Dihydrolysergic acid, dihydrolysergic amide, and a fourth metabolite formed through oxidative opening of the proline ring are considered minor metabolites. After intranasal administration, it has been found that metabolites represent 20-30% of plasma AUC.
Dihydroergotamine is metabolized in the liver, with metabolites predominantly excreted in the feces. (A2942)
Route of Elimination: The major excretory route of dihydroergotamine is via the bile in the feces.
Only 6%-7% of unchanged dihydroergotamine is excreted in the urine after intramuscular injection.
Half Life: 9 hours
Two theories have been proposed to explain the efficacy of 5-HT<sub>1D</sub> receptor agonists in migraine: 1) activation of 5-HT<sub>1D</sub> receptors located on intracranial blood vessels, including those on arterio-venous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache and 2) activation of 5-HT<sub>1D</sub> receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release.
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
When delivered intranasally, DHE has a bioavailability of approximately 40% with a tmax of 30-60 min.. Oral formulations have largely been unsuccessful due to a 1% bioavailability owing to a high degree of first-pass metabolism. Both intramuscular and intravenous administration produces 100% bioavailability with a tmax of 1-2 min and 24-34 min respectively.
来源:DrugBank
吸收、分配和排泄
消除途径
DHE主要通过肝脏代谢随后通过胆汁排泄。单次肌内注射剂量的6-7%通过尿液排出。
DHE is primarily eliminated through hepatic metabolism followed by biliary excretion. 6-7% of a single intramuscular dose is excreted in the urine.
来源:DrugBank
吸收、分配和排泄
分布容积
DHE具有800升的稳态分布容积。
DHE has a steady-state volume of distribution of 800 L.
来源:DrugBank
吸收、分配和排泄
清除
去氢表雄酮的总清除率为1.5升/小时，其中肾清除率贡献了0.1升/小时。
The total clearance of DHE is 1.5 L/h with renal clearance contributing 0.1 L/h.
[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.
[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.
[EN] SPIROLACTAM CGRP RECEPTOR ANTAGONISTS<br/>[FR] ANTAGONISTES DE RÉCEPTEUR DE CGRP À BASE DE SPIROLACTAME
申请人：MERCK SHARP & DOHME
公开号：WO2013169567A1
公开（公告）日：2013-11-14
The present invention is directed to spirolactam analogues which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
[EN] INDANE DERIVATIVES AS MGLUR7 MODULATORS<br/>[FR] DÉRIVÉS D'INDANE UTILISÉS COMME MODULATEURS DE MGLUR7
申请人：TAKEDA PHARMACEUTICALS CO
公开号：WO2017131221A1
公开（公告）日：2017-08-03
The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4a and R4b are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. The compounds of formula (I) are mGluR7 modulators.
[EN] IMIDAZOLINONE DERIVATIVES AS CGRP RECEPTOR ANTAGONISTS<br/>[FR] DÉRIVÉS D'IMIDAZOLINONE EN TANT QU'ANTAGONISTES DE RÉCEPTEURS CGRP
申请人：MERCK SHARP & DOHME
公开号：WO2010077752A1
公开（公告）日：2010-07-08
The present invention is directed to imidazolinone derivatives which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.
