Details of the Drug Combination

General Information of Drug Combination (ID: DCX6HRV)

• Drug Combination Name: Morphine + Methadone
• Indication: Cancer; Status: Phase 1 [1]
• Component Drugs:
  Morphine (DMRMS0L): Small molecular drug
  Methadone (DMTW6IU): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Morphine

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[2]
Chronic pain	MG30	Approved	[3]
Pain	MG30-MG3Z	Approved	[2]
Diarrhea	ME05.1	Investigative	[2]

Morphine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor mu (MOP)	TTKWM86	OPRM_HUMAN	Modulator	[8]

Morphine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]
Multidrug resistance-associated protein 3 (ABCC3)	DTQ3ZHF	MRP3_HUMAN	Substrate	[10]

Morphine Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[12]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[13]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[14]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[15]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[16]

Morphine Interacts with 22 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Response	[17]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Increases Response	[17]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[18]
LIM homeobox transcription factor 1-beta (LMX1B)	OTM8145D	LMX1B_HUMAN	Increases Expression	[19]
Krueppel-like factor 7 (KLF7)	OTS3YVA0	KLF7_HUMAN	Increases Expression	[20]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[21]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Increases Expression	[22]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[23]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Decreases Expression	[24]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[25]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[25]
Kappa-type opioid receptor (OPRK1)	OTXCZF4L	OPRK_HUMAN	Increases Activity	[26]
C-C motif chemokine 8 (CCL8)	OTCTWYN8	CCL8_HUMAN	Increases Secretion	[23]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Increases Secretion	[18]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Increases Phosphorylation	[21]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[27]
DNA damage-binding protein 2 (DDB2)	OTO8HVVB	DDB2_HUMAN	Increases Expression	[19]
Ninjurin-1 (NINJ1)	OTLRZ1EU	NINJ1_HUMAN	Increases Expression	[19]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[19]
Cocaine esterase (CES2)	OTC647SQ	EST2_HUMAN	Increases Chemical Synthesis	[28]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases ADR	[29]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases ADR	[29]

Indication(s) of Methadone

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[4]
Dry cough	MD12	Approved	[3]
Pain	MG30-MG3Z	Approved	[4]

Methadone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor (OPR)	TTN4QDT	NOUNIPROTAC	Agonist	[30]

Methadone Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[31]

Methadone Interacts with 10 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[32]
Aromatase (CYP19A1)	DEQX145	CP19A_HUMAN	Metabolism	[33]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[34]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[32]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[32]
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Metabolism	[35]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[32]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[32]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[32]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[32]

Methadone Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[36]
Alpha-1-acid glycoprotein 2 (ORM2)	OTRJGZP8	A1AG2_HUMAN	Affects Binding	[37]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[25]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[25]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Affects Localization	[38]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Pain	DCN4K8R	N. A.	Phase 1	[39]

References

• [1] ClinicalTrials.gov (NCT03324815) Methadone Associated With Morphine for Cancer Pain
• [2] Morphine FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] Methadone FDA Label
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• [37] Binding of disopyramide, methadone, dipyridamole, chlorpromazine, lignocaine and progesterone to the two main genetic variants of human alpha 1-acid glycoprotein: evidence for drug-binding differences between the variants and for the presence of two separate drug-binding sites on alpha 1-acid glycoprotein. Pharmacogenetics. 1996 Oct;6(5):403-15. doi: 10.1097/00008571-199610000-00004.
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• [39] ClinicalTrials.gov (NCT00558870) Role of Methadone As Co-Opioid Analgesic