Details of the Drug Combination

General Information of Drug Combination (ID: DC88923)

• Drug Combination Name: Clonidine + Enalapril
• Indication: Hypertension; Status: Phase 4 [1]
• Component Drugs:
  Clonidine (DM6RZ9Q): Small molecular drug
  Enalapril (DMNFUZR): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Clonidine

Disease Entry	ICD 11	Status	REF
Attention deficit hyperactivity disorder	6A05.Z	Approved	[2]
Hypertension	BA00-BA04	Approved	[3]
Neonatal abstinence syndrome	N.A.	Approved	[2]
Diabetic neuropathy	8C0Z	Phase 3	[4]

Clonidine Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor Alpha-2 (ADRA2)	TTQ8AFT	NOUNIPROTAC	Agonist	[7]
Membrane copper amine oxidase (AOC3)	TT7HC21	AOC3_HUMAN	Inhibitor	[8]

Clonidine Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[10]
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[10]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[10]

Clonidine Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[11]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[11]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[11]

Clonidine Interacts with 24 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases ADR	[12]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases ADR	[12]
G protein-activated inward rectifier potassium channel 1 (KCNJ3)	OTHQG16J	KCNJ3_HUMAN	Increases ADR	[12]
Apoptosis-inducing factor 1, mitochondrial (AIFM1)	OTKPWB7Q	AIFM1_HUMAN	Increases Expression	[13]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Activity	[14]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Increases Expression	[15]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[16]
Somatotropin (GH1)	OT92RTRD	SOMA_HUMAN	Increases Expression	[17]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Decreases Secretion	[18]
Apolipoprotein A-I (APOA1)	OT5THARI	APOA1_HUMAN	Decreases Expression	[19]
Apolipoprotein A-II (APOA2)	OTQ3HGTC	APOA2_HUMAN	Decreases Expression	[19]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[13]
Tumor necrosis factor alpha-induced protein 3 (TNFAIP3)	OTVLI4DD	TNAP3_HUMAN	Increases Expression	[20]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Secretion	[21]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[13]
Caspase-2 (CASP2)	OTUDYSPP	CASP2_HUMAN	Increases Activity	[13]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[13]
Tumor protein D52 (TPD52)	OTPKSK43	TPD52_HUMAN	Increases Expression	[20]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[13]
Programmed cell death protein 4 (PDCD4)	OTZ6NXUX	PDCD4_HUMAN	Decreases Expression	[20]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[13]
Delta-type opioid receptor (OPRD1)	OT164PA1	OPRD_HUMAN	Increases ADR	[12]
Myeloperoxidase (MPO)	OTOOXLIN	PERM_HUMAN	Increases ADR	[12]
Kappa-type opioid receptor (OPRK1)	OTXCZF4L	OPRK_HUMAN	Increases ADR	[12]

Indication(s) of Enalapril

Disease Entry	ICD 11	Status	REF
Congestive heart failure	BD10	Approved	[5]
Hypertension	BA00-BA04	Approved	[6]
Malignant essential hypertension	BA00	Approved	[5]

Enalapril Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin-converting enzyme (ACE)	TTL69WB	ACE_HUMAN	Inhibitor	[22]

Enalapril Interacts with 6 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[23]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[24]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[25]
Peptide transporter 2 (SLC15A2)	DT8QKNP	S15A2_HUMAN	Substrate	[26]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[27]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[23]

Enalapril Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[28]
Carboxylesterase 1 (CES1)	DEB30C5	EST1_HUMAN	Metabolism	[29]
Dipeptidase (pepV)	DEQMBHW	Q84BU9_LACLH	Metabolism	[30]

Enalapril Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases ADR	[12]
Solute carrier organic anion transporter family member 1B1 (SLCO1B1)	OTNEN8QK	SO1B1_HUMAN	Affects Abundance	[31]
Carbonic anhydrase 2 (CA2)	OTJRMUAG	CAH2_HUMAN	Decreases Activity	[32]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Activity	[33]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Decreases Expression	[34]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Decreases Expression	[35]
Erythropoietin (EPO)	OTZ90CN4	EPO_HUMAN	Decreases Expression	[34]
Angiogenin (ANG)	OT3ECS6P	ANGI_HUMAN	Decreases Expression	[36]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Decreases Expression	[37]
Somatotropin (GH1)	OT92RTRD	SOMA_HUMAN	Increases Response To Substance	[38]
ATP-binding cassette sub-family C member 4 (ABCC4)	OTO27PAL	MRP4_HUMAN	Increases Transport	[39]
B2 bradykinin receptor (BDKRB2)	OTOA9D3W	BKRB2_HUMAN	Increases ADR	[12]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Affects Response To Substance	[40]

References

• [1] ClinicalTrials.gov (NCT02177461) Telmisartan Compared With Enalapril in Elderly Patients With Blood Hypertension
• [2] Clonidine 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: 516).
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] Enalapril FDA Label
• [6] 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: 6322).
• [7] Noradrenergic alpha-2 receptor agonists reverse working memory deficits induced by the anxiogenic drug, FG7142, in rats. Pharmacol Biochem Behav. 2000 Nov;67(3):397-403.
• [8] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [9] Caco-2 permeability, P-glycoprotein transport ratios and brain penetration of heterocyclic drugs. Int J Pharm. 2003 Sep 16;263(1-2):113-22.
• [10] Influx Transport of Cationic Drug at the Blood-Retinal Barrier: Impact on the Retinal Delivery of Neuroprotectants. Biol Pharm Bull. 2017;40(8):1139-1145.
• [11] CYP2D6 mediates 4-hydroxylation of clonidine in vitro: implication for pregnancy-induced changes in clonidine clearance. Drug Metab Dispos. 2010 Sep;38(9):1393-6.
• [12] 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.
• [13] Clonidine Induces Apoptosis of Human Corneal Epithelial Cells through Death Receptors-Mediated, Mitochondria-Dependent Signaling Pathway. Toxicol Sci. 2017 Mar 1;156(1):252-260. doi: 10.1093/toxsci/kfw249.
• [14] The effect of clonidine and penbutolol, respectively on catecholamines in blood and urine, plasma renin activity and urinary aldosterone in hypertensive patients. Arch Int Pharmacodyn Ther. 1975 Feb;213(2):307-21.
• [15] Normalization of blood pressure and plasma concentrations of beta-endorphin and leucine-enkephalin in patients with primary hypertension after treatment with clonidine. J Cardiovasc Pharmacol. 1987;10 Suppl 12:S147-51.
• [16] Clonidine-induced gynecomastia and hyperprolactinemia in a 6-year-old child. J Clin Psychiatry. 2005 Dec;66(12):1616-7. doi: 10.4088/jcp.v66n1219f.
• [17] Assessment of MK-912, an alpha 2-adrenoceptor antagonist, with use of intravenous clonidine. Clin Pharmacol Ther. 1989 Jul;46(1):103-9. doi: 10.1038/clpt.1989.113.
• [18] Clonidine effect on insulin secretion and lipolysis in man. Acta Diabetol Lat. 1978 May-Aug;15(3-4):192-7. doi: 10.1007/BF02581064.
• [19] The effects of clonidine hydrochloride versus atenolol monotherapy on serum lipids, lipid subfractions, and apolipoproteins in mild hypertension. Am Heart J. 1990 Jul;120(1):172-9. doi: 10.1016/0002-8703(90)90175-w.
• [20] Human embryonic stem cell derived hepatocyte-like cells as a tool for in vitro hazard assessment of chemical carcinogenicity. Toxicol Sci. 2011 Dec;124(2):278-90. doi: 10.1093/toxsci/kfr225. Epub 2011 Aug 27.
• [21] Antihypertensive drugs clonidine, diazoxide, hydralazine and furosemide regulate the production of cytokines by placentas and peripheral blood mononuclear cells in normal pregnancy. J Hypertens. 2006 May;24(5):915-22. doi: 10.1097/01.hjh.0000222762.84605.03.
• [22] Determination of bezafibrate, methotrexate, cyclophosphamide, orlistat and enalapril in waste and surface waters using on-line solid-phase extracti... J Environ Monit. 2009 Apr;11(4):830-8.
• [23] Vectorial transport of enalapril by Oatp1a1/Mrp2 and OATP1B1 and OATP1B3/MRP2 in rat and human livers. J Pharmacol Exp Ther. 2006 Jul;318(1):395-402.
• [24] The modified dipeptide, enalapril, an angiotensin-converting enzyme inhibitor, is transported by the rat liver organic anion transport protein. Hepatology. 1998 Nov;28(5):1341-6.
• [25] The intestinal H+/peptide symporter PEPT1: structure-affinity relationships. Eur J Pharm Sci. 2004 Jan;21(1):53-60.
• [26] Ethanol inhibits functional activity of the human intestinal dipeptide transporter hPepT1 expressed in Xenopus oocytes. Alcohol Clin Exp Res. 2008 May;32(5):777-84.
• [27] Uptake of enalapril and expression of organic anion transporting polypeptide 1 in zonal, isolated rat hepatocytes. Drug Metab Dispos. 2000 Jul;28(7):801-6.
• [28] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [29] Absorption and cleavage of enalapril, a carboxyl ester prodrug, in the rat intestine: in vitro, in situ intestinal perfusion and portal vein cannulation models. Biopharm Drug Dispos. 2015 Sep;36(6):385-397.
• [30] Characterization and kinetic analysis of enzyme-substrate recognition by three recombinant lactococcal PepVs. Arch Biochem Biophys. 2006 Oct 15;454(2):137-45.
• [31] Effect of organic anion-transporting polypeptide 1B1 (OATP1B1) polymorphism on the single- and multiple-dose pharmacokinetics of enalapril in healthy Chinese adult men. Clin Ther. 2011 May;33(5):655-63. doi: 10.1016/j.clinthera.2011.04.018.
• [32] Captopril/enalapril inhibit promiscuous esterase activity of carbonic anhydrase at micromolar concentrations: An initro study. Chem Biol Interact. 2017 Mar 1;265:24-35.
• [33] A nonpeptide, piperidine renin inhibitor provides renal and cardiac protection in double-transgenic mice expressing human renin and angiotensinogen genes. Cardiovasc Drugs Ther. 2008 Dec;22(6):469-78. doi: 10.1007/s10557-008-6131-x. Epub 2008 Aug 5.
• [34] Worsening of anemia by angiotensin converting enzyme inhibitors and its prevention by antiestrogenic steroid in chronic hemodialysis patients. J Cardiovasc Pharmacol. 1989;13 Suppl 3:S27-30. doi: 10.1097/00005344-198900133-00007.
• [35] The effect of early converting enzyme inhibition on neurohumoral activation in acute myocardial infarction. Int J Cardiol. 1993 Nov;42(1):37-45. doi: 10.1016/0167-5273(93)90100-u.
• [36] Effects of enalapril maleate on blood pressure, renin-angiotensin-aldosterone system, and peripheral sympathetic activity in essential hypertension. Clin Ther. 1987;9(4):390-9.
• [37] Inhibition of the renin-angiotensin system downregulates tissue factor and vascular endothelial growth factor in human breast carcinoma cells. Thromb Res. 2012 Jun;129(6):736-42. doi: 10.1016/j.thromres.2011.11.047. Epub 2011 Dec 19.
• [38] Growth hormone aggravates renal abnormalities induced by neonatal enalapril treatment. Pediatr Nephrol. 2003 Sep;18(9):878-86. doi: 10.1007/s00467-003-1197-y. Epub 2003 Jul 23.
• [39] Multichannel liquid chromatography-tandem mass spectrometry cocktail method for comprehensive substrate characterization of multidrug resistance-associated protein 4 transporter. Pharm Res. 2007 Dec;24(12):2281-96.
• [40] Effect of enalapril and losartan on cytokines in patients with stable angina pectoris awaiting coronary artery bypass grafting and their interaction with polymorphisms in the interleukin-6 gene. Am J Cardiol. 2004 Sep 1;94(5):564-9. doi: 10.1016/j.amjcard.2004.05.017.