Details of the Drug Combination

General Information of Drug Combination (ID: DCKJF6Q)

• Drug Combination Name: Metamizole + Codeine
• Indication: Pain, Postoperative; Status: Phase 3 [1]
• Component Drugs:
  Metamizole (DM79GRO): Small molecular drug
  Codeine (DMJX6ZG): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Metamizole

Disease Entry	ICD 11	Status	REF
Fever	MG26	Withdrawn from market	[2]
Pain	MG30-MG3Z	Withdrawn from market	[2]

Metamizole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Prostaglandin G/H synthase 1 (COX-1)	TT8NGED	PGH1_HUMAN	Inhibitor	[5]

Metamizole Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
RNA cytidine acetyltransferase (hALP)	DEZV4AP	NAT10_HUMAN	Metabolism	[6]

Indication(s) of Codeine

Disease Entry	ICD 11	Status	REF
Allergic rhinitis	CA08.0	Approved	[3]
Common cold	CA00	Approved	[3]
Fever	MG26	Approved	[3]
Headache	8A80-8A84	Approved	[3]
Pain	MG30-MG3Z	Approved	[4]
Rhinitis	FA20	Approved	[3]
Cough	MD12	Phase 1	[4]

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	[7]

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	[8]

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	[9]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[10]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[11]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[12]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[13]
UDP-glucuronosyltransferase 2B4 (UGT2B4)	DENUPDX	UD2B4_HUMAN	Metabolism	[14]

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	[15]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[16]
Cocaine esterase (CES2)	OTC647SQ	EST2_HUMAN	Increases Hydrolysis	[17]

References

• [1] ClinicalTrials.gov (NCT04641338) Fixed Combination of Dipirone and Codeine Compared to the Isolated Use of Dipyrone and Codeine in Controlling Pain After Pelvic-abdominal Surgery.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Codeine FDA Label
• [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: 1673).
• [5] Mechanisms of action of paracetamol and related analgesics. Inflammopharmacology. 2003;11(4):401-13.
• [6] N-acetyltransferase 2 polymorphisms and susceptibility to infant leukemia with maternal exposure to dipyrone during pregnancy. Cancer Epidemiol Biomarkers Prev. 2010 Dec;19(12):3037-43.
• [7] Butorphanol: effects of a prototypical agonist-antagonist analgesic on kappa-opioid receptors. J Pharmacol Sci. 2005 Jun;98(2):109-16.
• [8] Association of Organic Cation Transporter 1 With Intolerance to Metformin in Type 2 Diabetes: A GoDARTS Study. Diabetes. 2015 May;64(5):1786-93.
• [9] 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.
• [10] 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.
• [11] Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet. 2009;48(11):689-723.
• [12] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [13] Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos. 1997 Jan;25(1):1-4.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.