Details of the Drug Combination

General Information of Drug Combination (ID: DCFFSPE)

• Drug Combination Name: Methyldopa + Labetalol
• Indication: Hypertension, Pregnancy-Induced; Status: Phase 4 [1]
• Component Drugs:
  Methyldopa (DM5I621): Small molecular drug
  Labetalol (DMK8U72): 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 Labetalol

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[3]
Hypertension, pregnancy-induced	N.A.	Approved	[4]
Malignant essential hypertension	BA00	Approved	[4]

Labetalol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor Alpha-1 (ADRA1)	TTG28O6	NOUNIPROTAC	Antagonist	[12]

Labetalol Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[14]

Labetalol Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[15]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[16]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[17]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[15]
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_HUMAN	Metabolism	[15]
UDP-glucuronosyltransferase 2B4 (UGT2B4)	DENUPDX	UD2B4_HUMAN	Metabolism	[15]

Labetalol Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases ADR	[18]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Activity	[19]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Decreases Expression	[20]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Decreases Activity	[19]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[21]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Decreases Activity	[22]
Beta-1 adrenergic receptor (ADRB1)	OTQBWN4U	ADRB1_HUMAN	Decreases Activity	[22]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Activity	[23]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Increases Activity	[24]

References

• [1] ClinicalTrials.gov (NCT02531490) Early Vascular Adjustments During Hypertensive Pregnancy
• [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] 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: 7207).
• [4] Labetalol 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] Beta-blockers in the treatment of hypertension: are there clinically relevant differences Postgrad Med. 2009 May;121(3):90-8.
• [13] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [14] Involvement of influx and efflux transport systems in gastrointestinal absorption of celiprolol. J Pharm Sci. 2009 Jul;98(7):2529-39.
• [15] Regulation of UDP-glucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination. Xenobiotica. 2008 Jan;38(1):62-75.
• [16] Comparison of verapamil, diltiazem, and labetalol on the bioavailability and metabolism of imipramine. J Clin Pharmacol. 1992 Feb;32(2):176-83.
• [17] Drug Interactions Flockhart Table
• [18] 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.
• [19] Hemodynamic and humoral effects of intravenous dilevalol in patients with moderate hypertension. Am J Cardiol. 1989 Jun 5;63(19):34I-37I. doi: 10.1016/0002-9149(89)90126-4.
• [20] Labetalol (AH5158), a competitive alpha- and beta-receptor blocking drug, in the management of hypertension. Aust N Z J Med. 1976 Aug;6(3 Suppl):83-8. doi: 10.1111/j.1445-5994.1976.tb03341.x.
• [21] Prolactin stimulation by intravenous labetalol is mediated inside the central nervous system. Clin Endocrinol (Oxf). 1982 Jun;16(6):615-9. doi: 10.1111/j.1365-2265.1982.tb03178.x.
• [22] Preclinical pharmacologic properties of dilevalol, an antihypertensive agent possessing selective beta 2 agonist-mediated vasodilation and beta antagonism. Am J Cardiol. 1989 Jun 5;63(19):3I-6I. doi: 10.1016/0002-9149(89)90120-3.
• [23] 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.
• [24] Prediction of off-target effects on angiotensin-converting enzyme 2. J Biomol Screen. 2011 Sep;16(8):878-85. doi: 10.1177/1087057111413919. Epub 2011 Aug 22.