Details of the Drug Combination

General Information of Drug Combination (ID: DC7PMTE)

• Drug Combination Name: Tadalafil + Sitaxsentan
• Indication: Pulmonary Arterial Hypertension; Status: Phase 1 [1]
• Component Drugs:
  Tadalafil (DMJZHT1): Small molecular drug
  Sitaxsentan (DMKM5HB): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Tadalafil

Disease Entry	ICD 11	Status	REF
Benign prostatic hyperplasia	GA90	Approved	[2]
Erectile dysfunction	HA01.1	Approved	[3]
Plasma cell myeloma	2A83.1	Approved	[2]
Pulmonary hypertension	BB01	Approved	[2]
Priapism	N.A.	Investigative	[2]

Tadalafil Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Phosphodiesterase 5A (PDE5A)	TTJ0IQB	PDE5A_HUMAN	Inhibitor	[5]

Tadalafil Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[6]

Tadalafil Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[7]

Tadalafil Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5A)	OTT8Q1AP	PDE5A_HUMAN	Decreases Activity	[8]

Indication(s) of Sitaxsentan

Disease Entry	ICD 11	Status	REF
Pulmonary arterial hypertension	BB01.0	Withdrawn from market	[4]

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] Tadalafil FDA Label
• [3] 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: 7299).
• [4] 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).
• [5] Pulmonary arterial hypertension: the most devastating vascular complication of systemic sclerosis. Rheumatology (Oxford). 2009 Jun;48 Suppl 3:iii25-31.
• [6] In Vitro P-Glycoprotein-Mediated Transport of Tadalafil: A Comparison with Sildenafil. Biol Pharm Bull. 2017;40(8):1314-1319.
• [7] Contribution of CYP3A isoforms to dealkylation of PDE5 inhibitors: a comparison between sildenafil N-demethylation and tadalafil demethylenation. Biol Pharm Bull. 2015;38(1):58-65.
• [8] Pharmacotherapy of erectile dysfunction: focus on cardiovascular safety. Expert Opin Drug Saf. 2005 May;4(3):531-40. doi: 10.1517/14740338.4.3.531.
• [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.