Roflumilast

Các tên gọi khác (3) :

Daliresp
ROF
Roflumilastum

Thuốc Gốc

Small Molecule

CAS: 162401-32-3

ATC: R03DX07

CTHH: C₁₇H₁₄Cl₂F₂N₂O₃

PTK: 403.207

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.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₁₇H₁₄Cl₂F₂N₂O₃

Phân tử khối

403.207

Monoisotopic mass

402.034954148

InChI

InChI=1S/C17H14Cl2F2N2O3/c18-11-6-22-7-12(19)15(11)23-16(24)10-3-4-13(26-17(20)21)14(5-10)25-8-9-1-2-9/h3-7,9,17H,1-2,8H2,(H,22,23,24)

InChI Key

InChIKey=MNDBXUUTURYVHR-UHFFFAOYSA-N

IUPAC Name

3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide

Traditional IUPAC Name

3-(cyclopropylmethoxy)-N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)benzamide

SMILES

FC(F)OC1=C(OCC2CC2)C=C(C=C1)C(=O)NC1=C(Cl)C=NC=C1Cl

Độ tan chảy

159.7

Độ hòa tan

insoluble (0.52-0.56 mg/L at 22°C)

logP

4.45

logS

-4.8

pKa (strongest acidic)

8.18

pKa (Strongest Basic)

2.4

PSA

60.45 Å²

Refractivity

93.92 m³·mol^-1

Polarizability

35.9 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

Number of Rings

Bioavailability

Rule of Five

true

Ghose Filter

true

MDDR-Like Rule

true

pKa

8.74

Dược Lực Học : 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.

Cơ Chế Tác Dụng : 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. 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.

Dược Động Học :

▧ 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.
▧ 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.

Độc Tính : Headache, weight loss, GI upset, insomnia, and loose stools.

Chỉ Định : 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.

Tương Tác Thuốc :

Abatacept Consider therapy modification due to enhanced immunosuppressive action.
Amiodarone Increases roflumilast levels.
Antithymocyte globulin Therapy may need to be modified due to enhanced immunosuppressive effects.
armodafinil Affects CYP1A2 metabolism; decreases level or effect of roflumilast.
Belatacept Consider modifying therapy due to enhanced immunosuppressive effect.
Belimumab Consider therapy modification due to enhanced immunosuppressive effect.
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.
Etanercept Due to enhanced immunosuppressive effects, therapy modification should be considered.
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.
Gemtuzumab ozogamicin Consider therapy modification due to enhanced immunosuppressive effect.
Glatiramer Acetate Consider therapy modification due to enhanced immunosuppressive effects.
Ibritumomab Consider modifying therapy due to enhanced immunosuppressive effect.
Infliximab Roflumilast enhances the adverse effects of immune suppressants thus a therapy modification should be considered.
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.
Obinutuzumab Consider therapy modification due to enhanced immunosuppressive effect.
Omalizumab Consider therapy modification due to enhanced immunosuppressive effects.
Omeprazole Affects CYP1A2 metabolism; decreases level or effect of roflumilast.
Oxcarbazepine Affects CYP3A4 metabolism, decreases level or effect of roflumilast.
Pegaspargase Consider therapy modification because pegaspargase enhances the immunosuppressive 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.
Rifampicin 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.

Liều Lượng & Cách Dùng : Tablet - Oral - 500mg

Dữ Kiện Thương Mại

Nhà Sản Xuất

Công ty : Forest Pharmaceuticals, Inc.

Sản phẩm biệt dược : Daliresp
Công ty : Takeda Pharmaceuticals International GmbH

Sản phẩm biệt dược : Daxas

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB01656

PubChem Compound

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=449193

PubChem Substance

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=10300323

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D05744

ChemSpider

http://www.chemspider.com/Chemical-Structure.395793.html

BindingDB

http://www.bindingdb.org/bind/chemsearch/marvin/MolStructure.jsp?monomerid=14774

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/0456-0095-30

Wikipedia

http://en.wikipedia.org/wiki/Roflumilast

Drugs.com

http://www.drugs.com/mtm/roflumilast.html

Bạn thấy hài lòng ?

Bạn chưa hài lòng ?

... loading