Details of the Drug Combination

General Information of Drug Combination (ID: DCYSU14)

• Drug Combination Name: Diltiazem + Oseltamivir
• Indication: Flu; Status: Phase 2 [1]
• Component Drugs:
  Diltiazem (DMAI7ZV): Small molecular drug
  Oseltamivir (DMGO72P): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Diltiazem

Disease Entry	ICD 11	Status	REF
Angina pectoris	BA40	Approved	[2]
Atrial fibrillation	BC81.3	Approved	[2]
Hypertension	BA00-BA04	Approved	[3]
Malignant essential hypertension	BA00	Approved	[2]

Diltiazem Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Voltage-gated calcium channel alpha-2/delta-1 (CACNA2D1)	TTFK1JQ	CA2D1_HUMAN	Blocker	[7]

Diltiazem Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]

Diltiazem Interacts with 7 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[10]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[11]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[12]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[13]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[10]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[14]

Diltiazem Interacts with 6 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases ADR	[15]
Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1)	OT8SPJNX	KCNQ1_HUMAN	Increases ADR	[15]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Increases ADR	[15]
Beta-1 adrenergic receptor (ADRB1)	OTQBWN4U	ADRB1_HUMAN	Increases Response	[16]
Potassium voltage-gated channel subfamily E member 1 (KCNE1)	OTZNQUW9	KCNE1_HUMAN	Increases ADR	[15]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Increases ADR	[15]

Indication(s) of Oseltamivir

Disease Entry	ICD 11	Status	REF
Influenza	1E30-1E32	Approved	[4]
Influenza virus infection	1E30-1E32	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[6]

Oseltamivir Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Influenza Neuraminidase (Influ NA)	TT50QJ3	NRAM_I33A0	Inhibitor	[17]

Oseltamivir Interacts with 5 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[18]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[19]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[20]
Organic anion transporter 1 (SLC22A6)	DTQ23VB	S22A6_HUMAN	Substrate	[21]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[21]

Oseltamivir Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Decreases Expression	[22]
Liver carboxylesterase 1 (CES1)	OT9L0LR8	EST1_HUMAN	Increases Metabolism	[23]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Response To Substance	[24]

References

• [1] ClinicalTrials.gov (NCT03212716) Efficiency of Antagonist Drugs of the Cellular Transcriptomic Signature of Influenza A Virus Infection.
• [2] Diltiazem 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: 2298).
• [4] Oseltamivir FDA Label
• [5] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [6] ClinicalTrials.gov (NCT04261270) A Randomized,Open,Controlled Clinical Study to Evaluate the Efficacy of ASC09F and Ritonavir for 2019-nCoV Pneumonia
• [7] Egr-1, the potential target of calcium channel blockers in cardioprotection with ischemia/reperfusion injury in rats. Cell Physiol Biochem. 2009;24(1-2):17-24.
• [8] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [9] Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos. 2002 Aug;30(8):883-91.
• [10] Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A. Drug Metab Dispos. 2000 Feb;28(2):125-30.
• [11] Significant impacts of CYP3A4*1G and CYP3A5*3 genetic polymorphisms on the pharmacokinetics of diltiazem and its main metabolites in Chinese adult kidney transplant patients. J Clin Pharm Ther. 2016 Jun;41(3):341-7.
• [12] FDA Drug Development and Drug Interactions
• [13] Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites. J Pharmacol Exp Ther. 1997 Jul;282(1):294-300.
• [14] Effects of CYP3A4 inhibition by diltiazem on pharmacokinetics and dynamics of diazepam in relation to CYP2C19 genotype status. Drug Metab Dispos. 2001 Oct;29(10):1284-9.
• [15] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [16] A common 1-adrenergic receptor polymorphism predicts favorable response to rate-control therapy in atrial fibrillation. J Am Coll Cardiol. 2012 Jan 3;59(1):49-56. doi: 10.1016/j.jacc.2011.08.061.
• [17] Current and future antiviral therapy of severe seasonal and avian influenza. Antiviral Res. 2008 Apr;78(1):91-102.
• [18] Nonclinical pharmacokinetics of oseltamivir and oseltamivir carboxylate in the central nervous system. Antimicrob Agents Chemother. 2009 Nov;53(11):4753-61.
• [19] Limited brain distribution of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), a pharmacologically active form of oseltamivir, by active efflux across the blood-brain barrier mediated by organic anion transporter 3 (Oat3/Slc22a8) and multidrug resistance-associated protein 4 (Mrp4/Abcc4). Drug Metab Dispos. 2009 Feb;37(2):315-21.
• [20] Oseltamivir (tamiflu) is a substrate of peptide transporter 1. Drug Metab Dispos. 2009 Aug;37(8):1676-81.
• [21] FDA Drug Development and Drug Interactions
• [22] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [23] In vitro inhibition of carboxylesterase 1 by Kava (Piper methysticum) Kavalactones. Chem Biol Interact. 2022 Apr 25;357:109883. doi: 10.1016/j.cbi.2022.109883. Epub 2022 Mar 9.
• [24] Interleukin-6 alters the cellular responsiveness to clopidogrel, irinotecan, and oseltamivir by suppressing the expression of carboxylesterases HCE1 and HCE2. Mol Pharmacol. 2007 Sep;72(3):686-94. doi: 10.1124/mol.107.036889. Epub 2007 May 30.