Details of the Drug Combination

General Information of Drug Combination (ID: DC2E6KU)

• Drug Combination Name: Phenprocoumon + Acenocoumarol
• Indication: Atrial Fibrillation; Status: Phase 3 [1]
• Component Drugs:
  Phenprocoumon (DMDO279): Small molecular drug
  Acenocoumarol (DMH75KV): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Phenprocoumon

Disease Entry	ICD 11	Status	REF
Myocardial infarction	BA41-BA43	Approved	[2]
Thrombosis	DB61-GB90	Approved	[3]
Venous thromboembolism	BD72	Investigative	[2]

Phenprocoumon Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Vitamin K epoxide reductase complex 1 (VKORC1)	TTEUC8H	VKOR1_HUMAN	Inhibitor	[6]

Phenprocoumon Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]

Phenprocoumon Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[8]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[9]

Phenprocoumon Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Decreases Activity	[10]

Indication(s) of Acenocoumarol

Disease Entry	ICD 11	Status	REF
Thrombosis	DB61-GB90	Approved	[4]

Acenocoumarol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Vitamin K epoxide reductase complex 1 (VKORC1)	TTEUC8H	VKOR1_HUMAN	Inhibitor	[12]

Acenocoumarol Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[13]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[14]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[15]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[14]

Acenocoumarol Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Affects Metabolism	[16]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Affects Response To Substance	[17]
Apolipoprotein E (APOE)	OTFOWL2H	APOE_HUMAN	Affects Response To Substance	[18]
Cytochrome P450 4F2 (CYP4F2)	OTKILAER	CP4F2_HUMAN	Affects Response To Substance	[19]
Cytochrome P450 2C18 (CYP2C18)	OTY687L9	CP2CI_HUMAN	Affects Response To Substance	[19]

References

• [1] ClinicalTrials.gov (NCT02942576) Edoxaban Treatment Versus Vitamin K Antagonist (VKA) in Patients With Atrial Fibrillation (AF) Undergoing Catheter Ablation
• [2] Phenprocoumon 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: 6839).
• [4] Drug information of Acenocoumarol, 2008. eduDrugs.
• [5] VKORC1 and VKORC1L1 have distinctly different oral anticoagulant dose-response characteristics and binding sites. Blood Adv. 2018 Mar 27;2(6):691-702.
• [6] [Oral anticoagulation and pharmacogenetics: importance in the clinical setting]. Rev Med Suisse. 2007 Sep 12;3(124):2030, 2033-4, 2036.
• [7] Role of P-glycoprotein in the uptake/efflux transport of oral vitamin K antagonists and rivaroxaban through the Caco-2 cell model. Basic Clin Pharmacol Toxicol. 2013 Oct;113(4):259-65.
• [8] Identification of cytochromes P450 2C9 and 3A4 as the major catalysts of phenprocoumon hydroxylation in vitro. Eur J Clin Pharmacol. 2004 May;60(3):173-82.
• [9] Genetic polymorphisms of cytochrome P450 2C9 causing reduced phenprocoumon (S)-7-hydroxylation in vitro and in vivo. Xenobiotica. 2004 Sep;34(9):847-59.
• [10] A Gene Expression Biomarker Predicts Heat Shock Factor 1 Activation in a Gene Expression Compendium. Chem Res Toxicol. 2021 Jul 19;34(7):1721-1737. doi: 10.1021/acs.chemrestox.0c00510. Epub 2021 Jun 25.
• [11] A vitamin K epoxide reductase-oxidase complex gene polymorphism (-1639G>A) and interindividual variability in the dose-effect of vitamin K antagonists. J Appl Genet. 2009;50(4):399-403. doi: 10.1007/BF03195700.
• [12] Evaluation of a reverse-hybridization StripAssay for the detection of genetic polymorphisms leading to acenocoumarol sensitivity. Mol Biol Rep. 2010 Apr;37(4):1693-7.
• [13] Possible interaction between topical terbinafine and acenocoumarol. Ann Pharmacother. 2009 Nov;43(11):1911-2.
• [14] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [15] Prediction of pharmacokinetic drug/drug interactions from In vitro data: interactions of the nonsteroidal anti-inflammatory drug lornoxicam with oral anticoagulants. Drug Metab Dispos. 2000 Feb;28(2):161-8.
• [16] Severe interaction between ritonavir and acenocoumarol. Ann Pharmacother. 2002 Apr;36(4):621-3.
• [17] Pharmacogenetics of acenocoumarol: CYP2C9, CYP2C19, CYP1A2, CYP3A4, CYP3A5 and ABCB1 gene polymorphisms and dose requirements. J Clin Pharm Ther. 2007 Dec;32(6):641-9.
• [18] Patients with an ApoE epsilon4 allele require lower doses of coumarin anticoagulants. Pharmacogenet Genomics. 2005 Feb;15(2):69-74. doi: 10.1097/01213011-200502000-00002.
• [19] A genome-wide association study of acenocoumarol maintenance dosage. Hum Mol Genet. 2009 Oct 1;18(19):3758-68. doi: 10.1093/hmg/ddp309. Epub 2009 Jul 4.