Details of the Drug Combination

General Information of Drug Combination (ID: DCFBBW7)

• Drug Combination Name: Codeine + Naloxegol
• Indication: Opioid-Induced Constipation; Status: Phase 4 [1]
• Component Drugs:
  Codeine (DMJX6ZG): Small molecular drug
  Naloxegol (DML0B41): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Codeine

Disease Entry	ICD 11	Status	REF
Allergic rhinitis	CA08.0	Approved	[2]
Common cold	CA00	Approved	[2]
Fever	MG26	Approved	[2]
Headache	8A80-8A84	Approved	[2]
Pain	MG30-MG3Z	Approved	[3]
Rhinitis	FA20	Approved	[2]
Cough	MD12	Phase 1	[3]

Codeine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor delta (OPRD1)	TT27RFC	OPRD_HUMAN	Agonist	[5]

Codeine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[6]

Codeine Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[8]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[9]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[10]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[11]
UDP-glucuronosyltransferase 2B4 (UGT2B4)	DENUPDX	UD2B4_HUMAN	Metabolism	[12]

Codeine Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Secretion	[13]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[14]
Cocaine esterase (CES2)	OTC647SQ	EST2_HUMAN	Increases Hydrolysis	[15]

Indication(s) of Naloxegol

Disease Entry	ICD 11	Status	REF
Opioid-induced constipation	DB32.1	Approved	[4]

Naloxegol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor mu (MOP)	TTKWM86	OPRM_HUMAN	Modulator	[16]

Naloxegol Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[17]

Naloxegol Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[18]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Constipation Drug Induced	DCJS6YP	N. A.	Phase 1	[19]

References

• [1] ClinicalTrials.gov (NCT05770960) Colonic Motor Patterns in Healthy Volunteers
• [2] Codeine 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: 1673).
• [4] 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: 7539).
• [5] Butorphanol: effects of a prototypical agonist-antagonist analgesic on kappa-opioid receptors. J Pharmacol Sci. 2005 Jun;98(2):109-16.
• [6] Association of Organic Cation Transporter 1 With Intolerance to Metformin in Type 2 Diabetes: A GoDARTS Study. Diabetes. 2015 May;64(5):1786-93.
• [7] Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8.
• [8] Evaluation of 3'-azido-3'-deoxythymidine, morphine, and codeine as probe substrates for UDP-glucuronosyltransferase 2B7 (UGT2B7) in human liver microsomes: specificity and influence of the UGT2B7*2 polymorphism. Drug Metab Dispos. 2003 Sep;31(9):1125-33.
• [9] Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet. 2009;48(11):689-723.
• [10] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [11] Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos. 1997 Jan;25(1):1-4.
• [12] Methadone inhibits CYP2D6 and UGT2B7/2B4 in vivo: a study using codeine in methadone- and buprenorphine-maintained subjects. Br J Clin Pharmacol. 2012 May;73(5):786-94.
• [13] Codeine induces human mast cell chemokine and cytokine production: involvement of G-protein activation. Allergy. 2007 May;62(5):532-8. doi: 10.1111/j.1398-9995.2007.01345.x.
• [14] Effects of common antitussive drugs on the hERG potassium channel current. J Cardiovasc Pharmacol. 2008 Dec;52(6):494-9. doi: 10.1097/FJC.0b013e31818eec8d.
• [15] Contribution of human esterases to the metabolism of selected drugs of abuse. Toxicol Lett. 2015 Jan 5;232(1):159-66. doi: 10.1016/j.toxlet.2014.10.026. Epub 2014 Oct 24.
• [16] 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
• [17] Tarascon Pocket Pharmacopoeia 2018 Classic Shirt-Pocket Edition.
• [18] Naloxegol: treatment for opioid-induced constipation in chronic non-cancer pain. Ann Pharmacother. 2015 Mar;49(3):360-5.
• [19] ClinicalTrials.gov (NCT02737059) Effect of Naloxegol on Gastric, Small Bowel, and Colonic Transit in Healthy Subjects