Details of the Drug Combination

General Information of Drug Combination (ID: DCK5H32)

• Drug Combination Name: Primidone + Oseltamivir
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Primidone (DM0WX6I): Small molecular drug
  Oseltamivir (DMGO72P): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 13.62
  Bliss Independence Score: 13.62
  Loewe Additivity Score: 27.1
  LHighest Single Agent (HSA) Score: 27.1

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Primidone

Disease Entry	ICD 11	Status	REF
Epilepsy	8A60-8A68	Approved	[2]
Epilepsy with generalized tonic-clonic seizures	N.A.	Approved	[3]
Focal epilepsy	N.A.	Approved	[3]

Primidone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
GABA(A) receptor alpha-1 (GABRA1)	TT1MPAY	GBRA1_HUMAN	Antagonist	[7]

Primidone Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[8]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[9]

Primidone Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases ADR	[10]
Serum paraoxonase/arylesterase 1 (PON1)	OTD0Z2XO	PON1_HUMAN	Decreases Activity	[11]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[12]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[13]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Decreases Expression	[13]
Protein S100-A8 (S100A8)	OTVMOB3F	S10A8_HUMAN	Increases Expression	[14]
Protein S100-A9 (S100A9)	OTOARHCS	S10A9_HUMAN	Increases Expression	[14]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Expression	[15]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[13]
Alkaline phosphatase, tissue-nonspecific isozyme (ALPL)	OTG7J4BP	PPBT_HUMAN	Increases ADR	[10]
Glutathione hydrolase 7 (GGT7)	OTW4IO3I	GGT7_HUMAN	Increases ADR	[10]

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	[16]

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	[17]
Multidrug resistance-associated protein 4 (ABCC4)	DTCSGPB	MRP4_HUMAN	Substrate	[18]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[19]
Organic anion transporter 1 (SLC22A6)	DTQ23VB	S22A6_HUMAN	Substrate	[20]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[20]

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	[13]
Liver carboxylesterase 1 (CES1)	OT9L0LR8	EST1_HUMAN	Increases Metabolism	[21]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Response To Substance	[22]

References

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• [2] 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: 5338).
• [3] Primidone FDA Label
• [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] DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6.
• [8] Prescribrt's digital referenve - Primidone - Drug Summary.
• [9] Clinically significant pharmacokinetic drug interactions between antiepileptic drugs. J Clin Pharm Ther. 1999 Apr;24(2):87-92.
• [10] 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.
• [11] Antiepileptic drugs: impacts on human serum paraoxonase-1. J Biochem Mol Toxicol. 2017 Jun;31(6).
• [12] Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals. Chem Res Toxicol. 2017 May 15;30(5):1219-1229. doi: 10.1021/acs.chemrestox.7b00048. Epub 2017 May 4.
• [13] 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.
• [14] Prediction of drug-induced liver injury using keratinocytes. J Appl Toxicol. 2017 Jul;37(7):863-872. doi: 10.1002/jat.3435. Epub 2017 Jan 31.
• [15] Elucidating mechanisms of toxicity using phenotypic data from primary human cell systems--a chemical biology approach for thrombosis-related side effects. Int J Mol Sci. 2015 Jan 5;16(1):1008-29. doi: 10.3390/ijms16011008.
• [16] Current and future antiviral therapy of severe seasonal and avian influenza. Antiviral Res. 2008 Apr;78(1):91-102.
• [17] Nonclinical pharmacokinetics of oseltamivir and oseltamivir carboxylate in the central nervous system. Antimicrob Agents Chemother. 2009 Nov;53(11):4753-61.
• [18] 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.
• [19] Oseltamivir (tamiflu) is a substrate of peptide transporter 1. Drug Metab Dispos. 2009 Aug;37(8):1676-81.
• [20] FDA Drug Development and Drug Interactions
• [21] 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.
• [22] 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.