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药品详细

Roflumilast(罗氟司特)

化学结构式图
中文名
罗氟司特
英文名
Roflumilast
分子式
C17H14Cl2F2N2O3
化学名
3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide
分子量
Average: 403.207
Monoisotopic: 402.034954148
CAS号
162401-32-3
ATC分类
R03D 未知
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor. Due to its selective inhibition of the PDE4 isoenzyme in lung cells, roflumilast is indicated for the management of chronic obstrtuctive pulmonary disease (COPD) exacerbations. Treatment with Roflumilast is associated with an increase in psychiatric adverse reactions, including suicide and suicidal attempts.

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    封装厂家
    参考
    Synthesis Reference

    http://en.wikipedia.org/wiki/File:Roflumilast_syn.png
    General Reference
    1. Meyers JA, Taverna J, Chaves J, Makkinje A, Lerner A: Phosphodiesterase 4 inhibitors augment levels of glucocorticoid receptor in B cell chronic lymphocytic leukemia but not in normal circulating hematopoietic cells. Clin Cancer Res. 2007 Aug 15;13(16):4920-7. Pubmed
    2. Sanz MJ, Cortijo J, Taha MA, Cerda-Nicolas M, Schatton E, Burgbacher B, Klar J, Tenor H, Schudt C, Issekutz AC, Hatzelmann A, Morcillo EJ: Roflumilast inhibits leukocyte-endothelial cell interactions, expression of adhesion molecules and microvascular permeability. Br J Pharmacol. 2007 Oct;152(4):481-492. Epub 2007 Aug 20. Pubmed
    3. Barone FC, Barton ME, White RF, Legos JJ, Kikkawa H, Shimamura M, Kuratani K, Kinoshita M: Inhibition of Phosphodiesterase Type 4 Decreases Stress-Induced Defecation in Rats and Mice. Pharmacology. 2007 Aug 28;81(1):11-17. Pubmed
    4. Chong J, Poole P, Leung B, Black PN: Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011 May 11;(5):CD002309. doi: 10.1002/14651858.CD002309.pub3. Pubmed
    5. Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbroker D, Bethke TD, Hiemstra PS, Rabe KF: Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax. 2007 Dec;62(12):1081-7. Epub 2007 Jun 15. Pubmed
    6. Thappali SR, Varanasi KV, Veeraraghavan S, Vakkalanka SK, Mukkanti K: Simultaneous quantitation of IC87114, roflumilast and its active metabolite roflumilast N-oxide in plasma by LC-MS/MS: application for a pharmacokinetic study. J Mass Spectrom. 2012 Dec;47(12):1612-9. doi: 10.1002/jms.3103. 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 Roflumilast is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. Roflumilast is not a bronchodilator and is not indicated for the relief of acute bronchospasm.
    Pharmacodynamics Roflumilast (and its active metabolite, roflumilast N-oxide) increases cyclic adenosine-3′, 5′-monophosphate (cAMP) in lung cells by inhibiting PDE4. Increased cAMP activates PKA, which inactivates transcription factors involved in inflammation. Romflumilast also decreases the amount of sputum neutrophils and eosinophils in COPD patients.
    Mechanism of action Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor which, due to its selective inhibition of the PDE4 isoenzyme, has potential antiinflammatory and antimodulatory effects in the pulmonary system. It is thought that the increased levels of intracellular cyclic AMP are responsible for the therapeutic actions of Roflumilast.
    Absorption After a 500mcg dose, the bioavailability of roflumilast is about 80%. In the fasted state, maximum plasma concentrations are reached in 0.5 to 2 hours. While in the fed state, Cmax is reduced by 40%, Tmax is increased by one hour, and total absorption is unchanged.
    Volume of distribution

    Roflumilast has a Vd of 2.9L/kg with a dose of 500mcg. Permeability of roflumilast across the blood-brain barrier appears to be poor in rat studies.
    Protein binding Roflumilast is 99% plasma protein bound.
    Metabolism
    Roflumilast is metabolized to roflumilast N-oxide, the active metabolite of roflumilast in humans, by CYP3A4 and CYP1A2.

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

    Substrate Enzymes Product
    Roflumilast
      		Roflumilast N-oxide Details
      Route of elimination Roflumilast is excreted 70% in the urine as roflumilast N-oxide.
      Half life Plasma half-life of roflumilast is 17 hours and its metabolite is 30 hours (oral dose).
      Clearance

      ~9.6 L/hour.
      Toxicity Headache, weight loss, GI upset, insomnia, and loose stools.
      Affected organisms
      • Humans and other mammals
      Pathways Not Available
      理化性质
      Properties
      State solid
      Experimental Properties
      Property Value Source
      melting point 159.7 Not Available
      water solubility insoluble (0.52-0.56 mg/L at 22°C) Not Available
      pKa 8.74 Not Available
      Predicted Properties
      Property Value Source
      water solubility 6.20e-03 g/l ALOGPS
      logP 4.47 ALOGPS
      logP 4.45 ChemAxon
      logS -4.8 ALOGPS
      pKa (strongest acidic) 8.18 ChemAxon
      pKa (strongest basic) 2.4 ChemAxon
      physiological charge 0 ChemAxon
      hydrogen acceptor count 4 ChemAxon
      hydrogen donor count 1 ChemAxon
      polar surface area 60.45 ChemAxon
      rotatable bond count 7 ChemAxon
      refractivity 93.92 ChemAxon
      polarizability 35.9 ChemAxon
      药物相互作用
      Drug Interaction
      Amiodarone Increases roflumilast levels.
      armodafinil Affects CYP1A2 metabolism; decreases level or effect of roflumilast.
      Bleomycin Roflumilast may enhance the immunosuppressive effect of Immunosuppressants.The Canadian product monograph (Daxas brand) recommends avoiding concurrent use with immunosuppressants. U.S. prescribing information (Daliresp brand) does not include such a warning.
      Bosentan Affects CYP3A4 metabolism, decreases level or effect of roflumilast.
      Carbamazepine Affects CYP3A4 metabolism, decreases level or effect of roflumilast. Also decreases the level or effect of roflumilast by affecting CYP1A2 metabolism.
      Carboplatin Roflumilast may enhance the immunosuppressive effect of immunosuppressants such as carboplatin. he Canadian roflumilast product monograph recommends avoiding concurrent use of roflumilast with any immunosuppressant medications due to the antiinflammatory/immune altering effects of roflumilast and the lack of relevant clinical experience with such use. Of note, this recommendation to avoid concurrent use does not apply to either inhaled corticosteroids (which have much more limited systemic immune-suppressing actions) or short-term systemic corticosteroid use. U.S. prescribing information does not contain this warning; but it appears prudent to avoid this combination when possible.
      Carmustine Roflumilast may enhance the immunosuppressive effect of immunosuppressants such as carmustine. The Canadian roflumilast product monograph recommends avoiding concurrent use of roflumilast with any immunosuppressant medications due to the antiinflammatory/immune altering effects of roflumilast and the lack of relevant clinical experience with such use. Of note, this recommendation to avoid concurrent use does not apply to either inhaled corticosteroids (which have much more limited systemic immune-suppressing actions) or short-term systemic corticosteroid use. U.S. prescribing information does not contain this warning; but it appears prudent to avoid this combination when possible.
      Chlorambucil Roflumilast may enhance the immunosuppressive effect of immunosuppressants such as chlorambucil. The Canadian roflumilast product monograph recommends avoiding concurrent use of roflumilast with any immunosuppressant medications due to the antiinflammatory/immune altering effects of roflumilast and the lack of relevant clinical experience with such use. Of note, this recommendation to avoid concurrent use does not apply to either inhaled corticosteroids (which have much more limited systemic immune-suppressing actions) or short-term systemic corticosteroid use. U.S. prescribing information does not contain this warning; but it appears prudent to avoid this combination when possible.
      Cimetidine Increases roflumilast levels.
      Cisplatin Roflumilast may enhance the immunosuppressive effect of immunosuppressants such as cisplatin. The Canadian roflumilast product monograph recommends avoiding concurrent use of roflumilast with any immunosuppressant medications due to the antiinflammatory/immune altering effects of roflumilast and the lack of relevant clinical experience with such use. Of note, this recommendation to avoid concurrent use does not apply to either inhaled corticosteroids (which have much more limited systemic immune-suppressing actions) or short-term systemic corticosteroid use. U.S. prescribing information does not contain this warning; but it appears prudent to avoid this combination when possible.
      Cladribine Roflumilast may enhance the immunosuppressive effect of immunosuppressants such as cladribine. The Canadian roflumilast product monograph recommends avoiding concurrent use of roflumilast with any immunosuppressant medications due to the antiinflammatory/immune altering effects of roflumilast and the lack of relevant clinical experience with such use. Of note, this recommendation to avoid concurrent use does not apply to either inhaled corticosteroids (which have much more limited systemic immune-suppressing actions) or short-term systemic corticosteroid use. U.S. prescribing information does not contain this warning; but it appears prudent to avoid this combination when possible.
      Clofarabine Roflumilast may enhance the immunosuppressive effect of Immunosuppressants. The Canadian roflumilast product monograph recommends avoiding concurrent use of roflumilast with any immunosuppressant medications due to the antiinflammatory/immune altering effects of roflumilast and the lack of relevant clinical experience with such use. Of note, this recommendation to avoid concurrent use does not apply to either inhaled corticosteroids (which have much more limited systemic immune-suppressing actions) or short-term systemic corticosteroid use. U.S. prescribing information does not contain this warning; but it appears prudent to avoid this combination when possible.
      Dexamethasone Affects CYP3A4 metabolism, decreases level or effect of roflumilast.
      Efavirenz Affects CYP3A4 metabolism, decreases level or effect of roflumilast.
      Erythromycin Increases roflumilast levels.
      Etravirine Affects CYP3A4 metabolism, decreases level or effect of roflumilast.
      Etravirine Roflumilast, when used concomitantly with etravirine, may experience a decrease in serum concentration. U.S prescribing information recommends avoiding concurrent therapy.
      Fluvoxamine Increases roflumilast levels.
      Fosphenytoin Affects CYP3A4 metabolism, decreases level or effect of roflumilast.
      Ketoconazole Increases roflumilast levels.
      Lopinavir Affects CYP1A2 metabolism; decreases level or effect of roflumilast.
      Modafinil Affects CYP1A2 metabolism; decreases level or effect of roflumilast.
      Nafcillin Affects CYP3A4 metabolism, decreases level or effect of roflumilast.
      Nevirapine Affects CYP3A4 metabolism, decreases level or effect of roflumilast.
      Omeprazole Affects CYP1A2 metabolism; decreases level or effect of roflumilast.
      Oxcarbazepine Affects CYP3A4 metabolism, decreases level or effect of roflumilast.
      Pentobarbital Affects CYP3A4 metabolism, decreases level or effect of roflumilast.
      Phenobarbital Affects CYP3A4 metabolism, decreases level or effect of roflumilast. Also decreases the level or effect of roflumilast by affecting CYP1A2 metabolism.
      Primidone Affects CYP3A4 metabolism, decreases level or effect of roflumilast. Also decreases the level or effect of roflumilast by affecting CYP1A2 metabolism.
      Rifabutin Affects CYP3A4 metabolism, decreases level or effect of roflumilast.
      Rifampin Affects CYP3A4 metabolism, decreases level or effect of roflumilast. Also decreases the level or effect of roflumilast by affecting CYP1A2 metabolism.
      Rifapentine Affects CYP3A4 metabolism, decreases level or effect of roflumilast.
      Ritonavir Affects CYP1A2 metabolism; decreases level or effect of roflumilast.
      St. John's Wort Affects CYP3A4 metabolism, decreases level or effect of roflumilast.
      Tofacitinib Roflumilast, when used in combination with tofacitinib, may increase the immunosuppressive effect of tofaciitinib and other immunosuppressive agents. It is recommended to modify therapy.
      Zafirlukast Increases roflumilast levels.
      食物相互作用
      Not Available

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