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药品详细

Rotigotine(罗替高汀)

化学结构式图
中文名
罗替高汀
英文名
Rotigotine
分子式
C19H25NOS
化学名
6-{propyl[2-(thiophen-2-yl)ethyl]amino}-5,6,7,8-tetrahydronaphthalen-1-ol
分子量
Average: 315.473
Monoisotopic: 315.165685117
CAS号
92206-54-7
ATC分类
N04B 未知
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

Rotigotine (Neupro) is a non-ergoline dopamine agonist indicated for the treatment of Parkinson’s disease (PD) and restless legs syndrome (RLS) in Europe and the United States. It is formulated as a once-daily transdermal patch which provides a slow and constant supply of the drug over the course of 24 hours.

Like other dopamine agonists, rotigotine has been shown to possess antidepressant effects and may be useful in the treatment of depression as well.

Rotigotine was developed by Aderis Pharmaceuticals. In 1998, Aderis licensed worldwide development and commercialization rights for rotigotine to the German pharmaceutical company Schwarz Pharma (today a subsidiary of the Belgian company UCB S.A.). The drug has been approved by the EMEA for use in Europe in 2006 and is today being sold in several European countries. In 2007, the Neupro patch was approved by the Food and Drug Administration (FDA) as the first transdermal treatment of Parkinson’s disease in the United States. However, as of 2008, Schwarz Pharma has recalled all Neupro patches in the United States and some in Europe because of problems with the delivery mechanism. Rotigotine has been authorized as a treatment for RLS since August 2008.

生产厂家
  • Schwarz biosciences inc
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Giladi N, Boroojerdi B, Korczyn AD, Burn DJ, Clarke CE, Schapira AH: Rotigotine transdermal patch in early Parkinson’s disease: A randomized, double-blind, controlled study versus placebo and ropinirole. Mov Disord. 2007 Oct 12;. Pubmed
  2. Chen JJ, Swope DM, Dashtipour K, Lyons KE: Transdermal rotigotine: a clinically innovative dopamine-receptor agonist for the management of Parkinson’s disease. Pharmacotherapy. 2009 Dec;29(12):1452-67. Pubmed
  3. Perez-Lloret S, Rey MV, Ratti PL, Rascol O: Rotigotine transdermal patch for the treatment of Parkinson’s Disease. Fundam Clin Pharmacol. 2013 Feb;27(1):81-95. doi: 10.1111/j.1472-8206.2012.01028.×. Epub 2012 Feb 9. Pubmed
  4. de Biase S, Merlino G, Lorenzut S, Valente M, Gigli GL: ADMET considerations for restless leg syndrome drug treatments. Expert Opin Drug Metab Toxicol. 2012 Oct;8(10):1247-61. doi: 10.1517/17425255.2012.708023. Epub 2012 Jul 18. Pubmed
剂型
规格
化合物类型
Type small molecule
Classes Not Available
Substructures Not Available
适应症
药理
Indication For use/treatment in neurologic disorders and parkinson's disease as well as moderate-to-severe primary Restless Legs Syndrome.
Pharmacodynamics Rotigotine is an agonist at all 5 dopamine receptor subtypes (D1-D5) but binds to the D3 receptor with the highest affinity. It is also an antagonist at α-2-adrenergic receptors and an agonist at the 5HT1A receptors. Rotigotine also inhibits dopamine uptake and prolactin secretion. There is no indication of a QT/QTc prolonging effect of Neupro in doses up to 24 mg/24 hours. The effects of Neupro at doses up to 24 mg/24 hours (supratherapeutic doses) on the QT/QTc interval was evaluated in a double-blind, randomized, placebo- and positive-controlled (moxifloxacin 400 mg IV, single dose) parallel-group trial with an overall treatment period of 52 days in male and female patients with advanced-stage Parkinson's disease. Assay sensitivity was confirmed by significant QTc prolongation by moxifloxacin.
Mechanism of action Rotigotine, a member of the dopamine agonist class of drugs, is delivered continuously through the skin (transdermal) using a silicone-based patch that is replaced every 24 hours. A dopamine agonist works by activating dopamine receptors in the body, mimicking the effect of the neurotransmitter dopamine. The precise mechanism of action of rotigotine as a treatment for Restless Legs Syndrome is unknown but is thought to be related to its ability to stimulate dopamine
Absorption Bioavailability varies depending on the application site. Differences in bioavailability were very small between the abdomen and hip (<1%). In contrast, the shoulder and thigh had a very large different in measured bioavailability (46%), with the shoulder showing the higher value. Tmax, 8 mg dose = 15 - 18 hours (it take approximately 3 hours until rotigotine reaches detectable levels in the plasma). The peak concentration cannot be observered. Steady state is reached in 2-3 days.
Volume of distribution

The weight normalized apparent volume of distribution, (Vd/F), in humans is approximately 84 L/kg after repeated dose administration.
Protein binding 92% in vitro and 89.5% in vivo.
Metabolism
Hepatic (CYP-mediated). Rotigotine is extensively and rapidly metabolized by conjugation and N-dealkylation. After intravenous dosing the predominant metabolites in human plasma are sulfate conjugates of rotigotine, glucuronide conjugates of rotigotine, sulfate conjugates of the N-despropyl-rotigotine and conjugates of N-desthienylethyl-rotigotine. Multiple CYP isoenzymes, sulfotransferases and two UDP-glucuronosyltransferases catalyze the metabolism of rotigotine.

Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us.

Substrate Enzymes Product
Rotigotine
    		N-despropyl-rotigotine Details
    Rotigotine
      		N-desthienylethyl-rotigotine Details
      Route of elimination Urine (71%), Fecal (23%). Most of rotigotine that is excreted in the urine is in the form of inactive conjugates. Unchanged drug made up less <1%.
      Half life After removal of the patch, plasma levels decreased with a terminal half-life of 5 to 7 hours. The pharmacokinetic profile showed a biphasic elimination with an initial half-life of 3 hours.
      Clearance Not Available
      Toxicity The most likely symptoms of overdose would be those related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting, hypotension, involuntary movements, hallucinations, confusion, convulsions, and other signs of excessive dopaminergic stimulation.
      Affected organisms
      • Humans and other mammals
      Pathways Not Available
      理化性质
      Properties
      State solid
      Experimental Properties
      Property Value Source
      logP 4.70 BIOBYTE STARLIST (2009)
      Predicted Properties
      Property Value Source
      water solubility 9.04e-03 g/l ALOGPS
      logP 5.01 ALOGPS
      logP 4.34 ChemAxon
      logS -4.5 ALOGPS
      pKa (strongest acidic) 10.03 ChemAxon
      pKa (strongest basic) 10.97 ChemAxon
      physiological charge 1 ChemAxon
      hydrogen acceptor count 2 ChemAxon
      hydrogen donor count 1 ChemAxon
      polar surface area 23.47 ChemAxon
      rotatable bond count 6 ChemAxon
      refractivity 94.56 ChemAxon
      polarizability 37.17 ChemAxon
      药物相互作用
      Drug Interaction
      Clobazam Concomitant therapy may potentiate adverse CNS effects such as increased sedation or respiratory depression. Monitor therapy closely.
      Dihydrocodeine Dihydrocodeine may enhance the sedative effect of rotigotine. It is recommended to monitor therapy.
      Enflurane Risk of sedation may increase with concomitant therapy. Monitor therapy closely.
      Ephedrine Risk of sedation may decrease with concomitant therapy. Monitor therapy closely.
      Fentanyl Pharmacodynamic synergism may increase the effects of rotigotine. Monitor therapy closely.
      Loxapine Pharmacodynamic antagonism may decrease the effects of rotigotine. Consider alternate therapy.
      Thiothixene Thiothixene may antaonize the effects of the anti-Parkinsonian agent, Rotigotine. Consider alternate therapy or monitor for decreased effects of both agents.
      Triprolidine The CNS depressants, Triprolidine and Rotigotine, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
      Ziprasidone The atypical antipsychotic, ziprasidone, may antagonize the effect of the dopamine agonist, rotigotine. Consider alternate therapy or monitor for worsening of movement disorder.
      Zuclopenthixol Antagonism may occur between zuclopenthixol, a dopamine D2 receptor antagonist, and rotigotine, a dopamine agonist. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of both agents if concurrent therapy is initiated, discontinued or dose(s) changed.
      食物相互作用
      • Because rotigotine is administered transdermally, food should not affect absorption, and the product may be administered without regard to the timing of meals.

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