DT-Web

DB01656 - Roflumilast


Identification
Name Roflumilast
Accession Number DB01656 (EXPT02802)
Type small molecule
Description 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.
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 403.207
Groups approved
Monoisotopic Weight 402.034954148
Pharmacology
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.
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.
Protein binding Roflumilast is 99% plasma protein bound.
Biotransformation 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.
Toxicity Headache, weight loss, GI upset, insomnia, and loose stools.
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of 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.
Food Interactions Not Available

Targets


cAMP-specific 3',5'-cyclic phosphodiesterase 4D
Name cAMP-specific 3',5'-cyclic phosphodiesterase 4D
Gene Name PDE4D
Pharmacological action unknown
Actions inhibitor
References
  • 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
  • Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. - Pubmed
DTHybrid score Not Available
cAMP-specific 3',5'-cyclic phosphodiesterase 4A
Name cAMP-specific 3',5'-cyclic phosphodiesterase 4A
Gene Name PDE4A
Pharmacological action unknown
Actions inhibitor
References
  • 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
DTHybrid score Not Available
cAMP-specific 3',5'-cyclic phosphodiesterase 4B
Name cAMP-specific 3',5'-cyclic phosphodiesterase 4B
Gene Name PDE4B
Pharmacological action unknown
Actions inhibitor
References
  • 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
DTHybrid score Not Available
cAMP-specific 3',5'-cyclic phosphodiesterase 4C
Name cAMP-specific 3',5'-cyclic phosphodiesterase 4C
Gene Name PDE4C
Pharmacological action unknown
Actions inhibitor
References
  • 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
DTHybrid score Not Available

Predictions


Id Partner name Gene Name Score
485 cGMP-inhibited 3',5'-cyclic phosphodiesterase A PDE3A 0.1292
779 High-affinity cAMP-specific 3',5'-cyclic phosphodiesterase 7A PDE7A 0.1228
691 cAMP-specific 3',5'-cyclic phosphodiesterase 7B PDE7B 0.1163
1178 Adenosine A2a receptor ADORA2A 0.1057
16 Adenosine A1 receptor ADORA1 0.1039
268 Adenosine A2b receptor ADORA2B 0.0725
6216 High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8A PDE8A 0.0701
695 cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A PDE10A 0.0645
6217 High affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8B PDE8B 0.0588
204 cGMP-specific 3',5'-cyclic phosphodiesterase PDE5A 0.0492
2684 Histidine triad nucleotide-binding protein 1 HINT1 0.0463
1792 Tissue-type plasminogen activator PLAT 0.0456
527 Prostacyclin receptor PTGIR 0.0423
3806 cGMP-dependent 3',5'-cyclic phosphodiesterase PDE2A 0.0391
73 Prostaglandin E2 receptor, EP1 subtype PTGER1 0.0388
6040 6-phosphogluconate dehydrogenase, decarboxylating PGD 0.0375
478 Voltage-dependent L-type calcium channel subunit alpha-1C CACNA1C 0.037
6160 Solute carrier organic anion transporter family member 3A1 SLCO3A1 0.0367
6152 Solute carrier organic anion transporter family member 2A1 SLCO2A1 0.0365
1632 Solute carrier organic anion transporter family member 2B1 SLCO2B1 0.0297
4200 Cytochrome P450 1A2 CYP1A2 0.0275
1830 5'-nucleotidase NT5E 0.0266
492 Histamine H1 receptor HRH1 0.0244
4122 Histone deacetylase 2 HDAC2 0.0228
777 Tumor necrosis factor TNF 0.0205
3957 Adenosine deaminase ADA 0.0185
5360 High-affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A PDE9A 0.0149
6143 Solute carrier family 22 member 7 SLC22A7 0.0143
6013 Cytochrome P450 2E1 CYP2E1 0.0129
2256 cGMP-inhibited 3',5'-cyclic phosphodiesterase B PDE3B 0.0122
4512 Cytochrome P450 3A4 CYP3A4 0.0122
2347 Proto-oncogene serine/threonine-protein kinase Pim-1 PIM1 0.0113
6037 Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamma PDE6G 0.011
851 5'-AMP-activated protein kinase subunit beta-2 PRKAB2 0.0105
388 AMP deaminase 1 AMPD1 0.0105
6136 Multidrug resistance-associated protein 5 ABCC5 0.0104
1291 cAMP response element-binding protein CREB1 0.0092
704 Long-chain-fatty-acid--CoA ligase 1 ACSL1 0.0091
386 Acetyl-coenzyme A synthetase, cytoplasmic ACSS2 0.0091
821 Acetyl-coenzyme A synthetase 2-like, mitochondrial ACSS1 0.0091
297 Adenylate cyclase type 1 ADCY1 0.0091
4198 Fructose-1,6-bisphosphatase 1 FBP1 0.0088
281 5'-AMP-activated protein kinase subunit beta-1 PRKAB1 0.0087
2164 Multidrug resistance-associated protein 4 ABCC4 0.0087
128 Adenine phosphoribosyltransferase APRT 0.0086
1898 Cytochrome P450 1B1 CYP1B1 0.0085
748 5'-AMP-activated protein kinase catalytic subunit alpha-1 PRKAA1 0.0084
6021 Adenosine kinase ADK 0.0081
10 Glycogen phosphorylase, liver form PYGL 0.0081
1588 Multidrug resistance protein 1 ABCB1 0.0077
6024 Cytochrome P450 1A1 CYP1A1 0.0069
5691 DTDP-4-DEHYDRORHAMNOSE 3,5-EPIMERASE RMLC rmlC 0.0067
3361 Serpin B5 SERPINB5 0.0067
5694 Transcription antiterminator licT licT 0.0067
4924 Cytochrome P450 2C8 CYP2C8 0.0061
4757 Cytochrome P450 2C9 CYP2C9 0.0056
4119 Cytochrome P450 2D6 CYP2D6 0.0055
56 Delta-aminolevulinic acid dehydratase ALAD 0.0054
2356 Delta-aminolevulinic acid dehydratase hemB 0.0054
3613 Delta-aminolevulinic acid dehydratase hemB 0.0054
3674 Delta-aminolevulinic acid dehydratase hemB 0.0054
2286 Isocitrate dehydrogenase [NADP] icd 0.0051
2302 Isocitrate dehydrogenase [NADP] icd 0.0051
2771 Isocitrate dehydrogenase [NADP] icd 0.0051
4534 Cytohesin-2 CYTH2 0.0048
814 Ryanodine receptor 1 RYR1 0.0048
3668 Maltose-binding periplasmic protein precursor malE 0.0047
5692 Calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1B PDE1B 0.0042
2592 Beta-galactosidase lacZ 0.0042
315 Arginase-1 ARG1 0.004
24 Thymidylate synthase TMP1 0.0033
359 Thymidylate synthase TYMS 0.0033
2626 Thymidylate synthase thyA 0.0033
2729 Thymidylate synthase thyA 0.0033
5352 Thymidylate synthase THYA 0.0033
6263 cAMP-dependent protein kinase catalytic subunit alpha PRKACA 0.0032
6107 Cytochrome P450 3A7 CYP3A7 0.0021
4118 Cytochrome P450 3A5 CYP3A5 0.002
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