Details of the Drug Combination

General Information of Drug Combination (ID: DC3P4O2)

• Drug Combination Name: Sildenafil + Sitaxsentan
• Indication: Pulmonary Arterial Hypertension; Status: Phase 1 [1]
• Component Drugs:
  Sildenafil (DM4YDAJ): Small molecular drug
  Sitaxsentan (DMKM5HB): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Sildenafil

Disease Entry	ICD 11	Status	REF
Alveolar capillary dysplasia with misalignment of pulmonary veins	N.A.	Approved	[2]
Erectile dysfunction	HA01.1	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[4]
Respiratory failure	CB41	Investigative	[2]

Sildenafil Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HUMAN phosphodiesterase type 5 (PDE5)	TTRYFSB	PDE5A_HUMAN	Inhibitor	[6]

Sildenafil Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3)	OTA6HYBA	GBB3_HUMAN	Increases Response	[7]
Angiotensin-converting enzyme (ACE)	OTDF1964	ACE_HUMAN	Increases Response	[8]

Indication(s) of Sitaxsentan

Disease Entry	ICD 11	Status	REF
Pulmonary arterial hypertension	BB01.0	Withdrawn from market	[5]

Sitaxsentan Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Endothelin A receptor (EDNRA)	TTKRD0G	EDNRA_HUMAN	Antagonist	[9]

Sitaxsentan Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[10]

Sitaxsentan Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[11]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[12]

References

• [1] ClinicalTrials.gov (NCT01244620) A Pharmacokinetic Drug-Drug Interaction (DDI) Study Between Sitaxsentan And Sildenafil, And Between Sitaxsentan And Tadalafil After Multiple Doses
• [2] Sildenafil FDA Label
• [3] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 206401.
• [4] ClinicalTrials.gov (NCT04304313) A Pilot Study of Sildenafil in COVID-19. U.S. National Institutes of Health.
• [5] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 3950).
• [6] Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus. J Virol. 2005 Feb;79(3):1966-9. doi: 10.1128/JVI.79.3.1966-1969.2005.
• [7] Sildenafil response is influenced by the G protein beta 3 subunit GNB3 C825T polymorphism: a pilot study. J Urol. 2003 Mar;169(3):1048-51. doi: 10.1097/01.ju.0000058369.72348.ba.
• [8] ACE gene I/D and NOS3 G894T polymorphisms and response to sildenafil in men with erectile dysfunction. Urology. 2003 Jul;62(1):152-7. doi: 10.1016/s0090-4295(03)00137-7.
• [9] Emerging treatments for pulmonary arterial hypertension. Expert Opin Emerg Drugs. 2006 Nov;11(4):609-19.
• [10] Interaction of acenocoumarol and sitaxentan in pulmonary arterial hypertension. Eur J Clin Invest. 2009 Jun;39 Suppl 2:14-8.
• [11] Bioactivation of sitaxentan in liver microsomes, hepatocytes, and expressed human P450s with characterization of the glutathione conjugate by liquid chromatography tandem mass spectrometry. Chem Res Toxicol. 2013 Jun 17;26(6):926-36.
• [12] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.