Details of the Drug Combination

General Information of Drug Combination (ID: DCZIT6V)

• Drug Combination Name: VR-776 + Oseltamivir
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  VR-776 (DMFQWNI): Small molecular drug
  Oseltamivir (DMGO72P): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 1.36
  Bliss Independence Score: 1.36
  Loewe Additivity Score: 17.02
  LHighest Single Agent (HSA) Score: 17.02

Molecular Interaction Atlas of This Drug Combination

Indication(s) of VR-776

Disease Entry	ICD 11	Status	REF
Premature ejaculation	HA03.0Z	Discontinued in Phase 1	[2]

VR-776 Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[6]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[7]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[8]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[9]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[10]

Indication(s) of Oseltamivir

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

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	[11]

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	[12]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[13]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[14]
Organic anion transporter 1 (SLC22A6)	DTQ23VB	S22A6_HUMAN	Substrate	[15]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[15]

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	[16]
Liver carboxylesterase 1 (CES1)	OT9L0LR8	EST1_HUMAN	Increases Metabolism	[17]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Response To Substance	[18]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [2] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022099)
• [3] Oseltamivir FDA Label
• [4] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [5] ClinicalTrials.gov (NCT04261270) A Randomized,Open,Controlled Clinical Study to Evaluate the Efficacy of ASC09F and Ritonavir for 2019-nCoV Pneumonia
• [6] Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol. 2007 Jul;151(6):737-48.
• [7] Erythromycin interaction with risperidone or clomipramine in an adolescent. J Child Adolesc Psychopharmacol. 1996 Summer;6(2):133-8.
• [8] Role of human UGT2B10 in N-glucuronidation of tricyclic antidepressants, amitriptyline, imipramine, clomipramine, and trimipramine. Drug Metab Dispos. 2010 May;38(5):863-70.
• [9] The biotransformation of clomipramine in vitro, identification of the cytochrome P450s responsible for the separate metabolic pathways. J Pharmacol Exp Ther. 1996 Jun;277(3):1659-64.
• [10] Serum clomipramine and desmethylclomipramine levels in a CYP2C19 and CYP2D6 intermediate metabolizer. Pharmacogenomics. 2017 May;18(7):601-605.
• [11] Current and future antiviral therapy of severe seasonal and avian influenza. Antiviral Res. 2008 Apr;78(1):91-102.
• [12] Nonclinical pharmacokinetics of oseltamivir and oseltamivir carboxylate in the central nervous system. Antimicrob Agents Chemother. 2009 Nov;53(11):4753-61.
• [13] 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.
• [14] Oseltamivir (tamiflu) is a substrate of peptide transporter 1. Drug Metab Dispos. 2009 Aug;37(8):1676-81.
• [15] FDA Drug Development and Drug Interactions
• [16] 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.
• [17] 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.
• [18] 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.