Details of the Drug Combination

General Information of Drug Combination (ID: DC2ETS3)

• Drug Combination Name: Methyldopa + Magnesium Sulfate
• Indication: Pre-eclampsia; Status: Phase 1 [1]
• Component Drugs:
  Methyldopa (DM5I621): Small molecular drug
  Magnesium Sulfate (DMVEK07): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Methyldopa

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[2]

Methyldopa Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dopamine D2 receptor (D2R)	TTEX248	DRD2_HUMAN	Agonist	[5]

Methyldopa Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[6]
Sulfotransferase 1A1 (SULT1A1)	DEYWLRK	ST1A1_HUMAN	Metabolism	[7]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[6]
Thiopurine methyltransferase (TPMT)	DEFQ8VO	TPMT_HUMAN	Metabolism	[8]

Methyldopa Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Glutathione S-transferase A1 (GSTA1)	OTA7K5XA	GSTA1_HUMAN	Decreases Activity	[9]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Decreases Activity	[9]
Glutathione S-transferase Mu 1 (GSTM1)	OTSBF2MO	GSTM1_HUMAN	Decreases Activity	[9]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[10]
Catechol O-methyltransferase (COMT)	OTPWKTQG	COMT_HUMAN	Increases Methylation	[11]

Indication(s) of Magnesium Sulfate

Disease Entry	ICD 11	Status	REF
Acute pain	MG31	Approved	[3]
Familial primary hypomagnesemia	N.A.	Approved	[4]
Hypertension, pregnancy-induced	N.A.	Approved	[4]
Mild pre-eclampsia	N.A.	Approved	[4]
Non-arteritic anterior ischemic optic neuropathy	9C40.40	Approved	[4]
Pain	MG30-MG3Z	Approved	[4]
Severe pre-eclampsia	N.A.	Approved	[4]
Traumatic brain injury	NA07.Z	Approved	[4]

Magnesium Sulfate Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
N-methyl-D-aspartate receptor (NMDAR)	TT9IK2Z	NOUNIPROTAC	Antagonist	[12]

Magnesium Sulfate Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Kallikrein-8 (KLK8)	OTGVGHXY	KLK8_HUMAN	Increases Activity	[13]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Activity	[14]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[15]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[15]

References

• [1] ClinicalTrials.gov (NCT01911494) Community Level Interventions for Pre-eclampsia
• [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: 5217).
• [3] Emerging drugs for acute ischemic stroke. Expert Opin Emerg Drugs. 2009 Mar;14(1):33-42.
• [4] Magnesium Sulfate FDA Label
• [5] Centrally acting antihypertensive agents: an update. J Clin Hypertens (Greenwich). 2007 May;9(5):399-405.
• [6] Lack of interaction between amiodarone and mexiletine in cardiac arrhythmia patients. J Clin Pharmacol. 2002 Mar;42(3):342-6.
• [7] Platelet phenol sulfotransferase and erythrocyte catechol-O-methyltransferase activities: correlation with methyldopa metabolism. Clin Pharmacol Ther. 1984 Jan;35(1):55-63.
• [8] Identification, characterization, and ontogenic study of a catechol O-methyltransferase from zebrafish. Aquat Toxicol. 2011 Mar;102(1-2):18-23.
• [9] Inhibition of human glutathione S-transferases by dopamine, alpha-methyldopa and their 5-S-glutathionyl conjugates. Chem Biol Interact. 1994 Jan;90(1):87-99.
• [10] Neonatal effects of methyldopa therapy in pregnancy hypertension. Acta Paediatr Hung. 1991;31(1):53-65.
• [11] Molecular mechanisms controlling the rate and specificity of catechol O-methylation by human soluble catechol O-methyltransferase. Mol Pharmacol. 2001 Feb;59(2):393-402. doi: 10.1124/mol.59.2.393.
• [12] Magnesium sulfate diminishes the effects of amide local anesthetics in rat sciatic-nerve block. Reg Anesth Pain Med. 2007 Jul-Aug;32(4):288-95.
• [13] Activation and enzymatic characterization of recombinant human kallikrein 8. Biol Chem. 2006 Jun;387(6):723-31. doi: 10.1515/BC.2006.091.
• [14] Haemodynamic and endocrine effects of deliberate hypotension with magnesium sulphate for cerebral-aneurysm surgery. Eur J Anaesthesiol. 1991 Mar;8(2):115-21.
• [15] Profiling the immunotoxicity of chemicals based on in vitro evaluation by a combination of the Multi-ImmunoTox assay and the IL-8 Luc assay. Arch Toxicol. 2018 Jun;92(6):2043-2054. doi: 10.1007/s00204-018-2199-7. Epub 2018 Mar 29.