Details of the Drug Combination

General Information of Drug Combination (ID: DC4W0T5)

• Drug Combination Name: Metyrapone + Hydrocortisone
• Indication: Glucocorticoid Effect; Status: Phase 1 [1]
• Component Drugs:
  Metyrapone (DMI7FVQ): Small molecular drug
  Hydrocortisone (DMGEMB7): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Metyrapone

Disease Entry	ICD 11	Status	REF
Cushing disease	5A70	Approved	[2]

Metyrapone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Steroid 11-beta-hydroxylase (CYP11B1)	TTIQUX7	C11B1_HUMAN	Inhibitor	[7]

Metyrapone Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1)	OT6EBDHM	DHB1_HUMAN	Decreases Expression	[8]
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2)	OT02MSKN	3BHS2_HUMAN	Decreases Expression	[8]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Increases Expression	[9]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[10]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Increases Expression	[11]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Increases Activity	[10]
Dehydrogenase/reductase SDR family member 7 (DHRS7)	OTV729DT	DHRS7_HUMAN	Increases Reduction	[12]

Indication(s) of Hydrocortisone

Disease Entry	ICD 11	Status	REF
Acne vulgaris	ED80	Approved	[3]
Acute adrenal insufficiency	N.A.	Approved	[3]
Addison disease	5A74.0	Approved	[3]
Allergic rhinitis	CA08.0	Approved	[3]
Angioedema	4A00.15	Approved	[3]
Aspiration pneumonitis	N.A.	Approved	[3]
Autoimmune haemolytic anaemia	3A20	Approved	[3]
Blepharoconjunctivitis	N.A.	Approved	[3]
Bursitis	N.A.	Approved	[3]
Cerebral edema	8D60.1	Approved	[3]
Corneal abrasion	NA06.4	Approved	[3]
Corneal ulcer	9A76	Approved	[3]
Crohn disease	DD70	Approved	[3]
Dermatitis herpetiformis	EB44	Approved	[3]
Diamond-Blackfan anemia	N.A.	Approved	[3]
Disorder of orbital region	N.A.	Approved	[3]
Erythema multiforme	N.A.	Approved	[3]
Exanthem	N.A.	Approved	[3]
Gingival disorder	N.A.	Approved	[3]
Granuloma annulare	N.A.	Approved	[3]
Inflammation	1A00-CA43.1	Approved	[4]
Inflammatory bowel disease	DD72	Approved	[3]
Keratitis	N.A.	Approved	[3]
Malignant otitis externa caused by Pseudomonas aeruginosa	N.A.	Approved	[3]
Multiple sclerosis	8A40	Approved	[3]
Mycosis fungoides	2B01	Approved	[3]
Primary cutaneous T-cell lymphoma	N.A.	Approved	[3]
Proctitis	DB33.Z	Approved	[3]
Psoriasis	EA90	Approved	[3]
Psoriatic arthritis	FA21	Approved	[3]
Rheumatic heart disease	N.A.	Approved	[3]
Rosacea	ED90.0	Approved	[3]
Sarcoidosis	4B20.5	Approved	[3]
Serum sickness	N.A.	Approved	[3]
Severe asthma	CA23	Approved	[3]
Systemic lupus erythematosus	4A40.0	Approved	[3]
Tinea corporis	1F28.Y	Approved	[3]
Tinea cruris	1F28.3	Approved	[3]
Ulcerative colitis	DD71	Approved	[3]
Viral pneumonia	N.A.	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[5]
Congenital adrenal hyperplasia	5A71.01	Phase 2	[6]
Acquired thrombocytopenia	N.A.	Investigative	[3]
Asthma	CA23	Investigative	[3]
Beta-thalassemia major	N.A.	Investigative	[3]
Classic Hodgkin lymphoma	N.A.	Investigative	[3]
Iridocyclitis	N.A.	Investigative	[3]
Phobic disorder	N.A.	Investigative	[3]
Rheumatoid arthritis	FA20	Investigative	[3]
Synovitis	N.A.	Investigative	[3]
Tinea pedis	1F28.2	Investigative	[3]
Trichinellosis	N.A.	Investigative	[3]
Uveitis	9A96.Z	Investigative	[3]

Hydrocortisone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Glucocorticoid receptor (NR3C1)	TTYRL6O	GCR_HUMAN	Modulator	[16]

Hydrocortisone 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]

Hydrocortisone Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[18]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[19]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[20]
Steroid 11-beta-hydroxylase (CYP11B1)	DEPE0RD	C11B1_HUMAN	Metabolism	[21]
Aldosterone synthase (CYP11B2)	DE6TYUK	C11B2_HUMAN	Metabolism	[21]

Hydrocortisone Interacts with 58 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Secretion	[22]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Secretion	[23]
GDH/6PGL endoplasmic bifunctional protein (H6PD)	OTO7TNDD	G6PE_HUMAN	Increases Expression	[24]
Disintegrin and metalloproteinase domain-containing protein 12 (ADAM12)	OTZKOTDB	ADA12_HUMAN	Decreases Expression	[25]
Mitogen-activated protein kinase kinase kinase 7 (MAP3K7)	OTUXEASC	M3K7_HUMAN	Decreases Expression	[25]
Integrin alpha-10 (ITGA10)	OTM0V5AO	ITA10_HUMAN	Increases Expression	[25]
Insulin-like growth factor-binding protein 5 (IGFBP5)	OTRE5V0C	IBP5_HUMAN	Decreases Expression	[25]
Adhesion G protein-coupled receptor E5 (ADGRE5)	OTTSB84Q	AGRE5_HUMAN	Decreases Expression	[25]
Metallothionein-1X (MT1X)	OT9AKFVS	MT1X_HUMAN	Increases Expression	[25]
Collagen alpha-1(VII) chain (COL7A1)	OT3MIRZJ	CO7A1_HUMAN	Decreases Expression	[25]
Peptidyl-prolyl cis-trans isomerase FKBP5 (FKBP5)	OT404F9K	FKBP5_HUMAN	Increases Expression	[25]
Nuclear receptor subfamily 6 group A member 1 (NR6A1)	OTFZOOQ9	NR6A1_HUMAN	Decreases Expression	[25]
Protein prune homolog 2 (PRUNE2)	OTGW2974	PRUN2_HUMAN	Decreases Expression	[25]
Adhesion G-protein coupled receptor G1 (ADGRG1)	OTQBB8NT	AGRG1_HUMAN	Decreases Expression	[25]
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1 (HSD3B1)	OTNAZVKB	3BHS1_HUMAN	Affects Binding	[26]
Steroidogenic acute regulatory protein, mitochondrial (STAR)	OTFEZ5AI	STAR_HUMAN	Decreases Expression	[27]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Increases Expression	[27]
Basic helix-loop-helix ARNT-like protein 1 (BMAL1)	OTMI12L2	BMAL1_HUMAN	Decreases Expression	[15]
Dihydroxyacetone phosphate acyltransferase (GNPAT)	OTF6LWPO	GNPAT_HUMAN	Increases Expression	[13]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Increases Expression	[28]
Period circadian protein homolog 1 (PER1)	OTVQF3WX	PER1_HUMAN	Increases Expression	[15]
Trehalase (TREH)	OTJE0NOY	TREA_HUMAN	Decreases Activity	[29]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Expression	[30]
Antithrombin-III (SERPINC1)	OTDFATG0	ANT3_HUMAN	Increases Expression	[31]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Increases Expression	[32]
Pro-neuropeptide Y (NPY)	OT4ICV3P	NPY_HUMAN	Affects Expression	[33]
Annexin A1 (ANXA1)	OT5OFDJC	ANXA1_HUMAN	Increases Expression	[13]
Kallikrein-1 (KLK1)	OTFGP3UR	KLK1_HUMAN	Increases Export	[32]
Involucrin (IVL)	OT4VPNGY	INVO_HUMAN	Decreases Expression	[34]
Pulmonary surfactant-associated protein B (SFTPB)	OTOHS07E	PSPB_HUMAN	Increases Expression	[35]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Increases Expression	[36]
Pulmonary surfactant-associated protein C (SFTPC)	OTIZJD09	PSPC_HUMAN	Increases Expression	[35]
C-C motif chemokine 4 (CCL4)	OT6B8P25	CCL4_HUMAN	Increases Expression	[36]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Expression	[36]
Filaggrin (FLG)	OTE9QDV6	FILA_HUMAN	Decreases Expression	[34]
Loricrin (LORICRIN)	OTFRPVEO	LORI_HUMAN	Decreases Expression	[34]
Cadherin-5 (CDH5)	OTVX0E1Q	CADH5_HUMAN	Increases Localization	[13]
T-lymphocyte activation antigen CD80 (CD80)	OTJBLUQE	CD80_HUMAN	Decreases Expression	[37]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Increases Localization	[13]
Amiloride-sensitive sodium channel subunit alpha (SCNN1A)	OTE2KVZV	SCNNA_HUMAN	Increases Expression	[38]
Carnitine O-palmitoyltransferase 1, liver isoform (CPT1A)	OTI862QH	CPT1A_HUMAN	Decreases Expression	[39]
Amiloride-sensitive sodium channel subunit beta (SCNN1B)	OT61QQTL	SCNNB_HUMAN	Increases Expression	[38]
Amiloride-sensitive sodium channel subunit gamma (SCNN1G)	OTSJYQVQ	SCNNG_HUMAN	Increases Expression	[38]
Ras-related protein Rap-1A (RAP1A)	OT5RH6TI	RAP1A_HUMAN	Increases Expression	[13]
Tight junction protein ZO-1 (TJP1)	OTBDCUPK	ZO1_HUMAN	Increases Localization	[13]
Acetyl-CoA carboxylase 1 (ACACA)	OT5CQPZY	ACACA_HUMAN	Increases Expression	[39]
Splicing factor 1 (SF1)	OTLEDM2S	SF01_HUMAN	Decreases Expression	[40]
Cryptochrome-1 (CRY1)	OTTGAJT0	CRY1_HUMAN	Increases Expression	[15]
Atypical chemokine receptor 1 (ACKR1)	OT9M11LX	ACKR1_HUMAN	Increases Expression	[13]
Occludin (OCLN)	OTSUTVWL	OCLN_HUMAN	Increases Expression	[13]
Patatin-like phospholipase domain-containing protein 2 (PNPLA2)	OTR3ERMR	PLPL2_HUMAN	Decreases Expression	[39]
TSC22 domain family protein 3 (TSC22D3)	OT03UM03	T22D3_HUMAN	Increases Expression	[13]
Oxytocin-neurophysin 1 (OXT)	OT48M72Z	NEU1_HUMAN	Affects Abundance	[41]
Aldo-keto reductase family 1 member D1 (AKR1D1)	OTBDJ6RL	AK1D1_HUMAN	Increases Reduction	[42]
Histone-binding protein RBBP7 (RBBP7)	OTLB56HX	RBBP7_HUMAN	Affects Response To Substance	[43]
Glycodelin (PAEP)	OTQA0NV4	PAEP_HUMAN	Increases Metabolism	[44]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Increases Abundance	[45]
T-box transcription factor TBX19 (TBX19)	OTXEMR2U	TBX19_HUMAN	Decreases Abundance	[46]

References

• [1] ClinicalTrials.gov (NCT05167084) Acute Consequences Of Food-induced Glucocorticoid Secretion In Healthy Individuals
• [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: 5224).
• [3] Hydrocortisone 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: 2868).
• [5] Hydrocortisone for COVID-19 and Severe Hypoxia (COVID STEROID)
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Effects of 3-MeSO2-DDE and some CYP inhibitors on glucocorticoid steroidogenesis in the H295R human adrenocortical carcinoma cell line. Toxicol In Vitro. 2002 Apr;16(2):113-21.
• [8] The H295R system for evaluation of endocrine-disrupting effects. Ecotoxicol Environ Saf. 2006 Nov;65(3):293-305.
• [9] Induction of ABCC3 (MRP3) by pregnane X receptor activators. Drug Metab Dispos. 2003 Nov;31(11):1296-9. doi: 10.1124/dmd.31.11.1296.
• [10] In vivo and mechanistic evidence of nuclear receptor CAR induction by artemisinin. Eur J Clin Invest. 2006 Sep;36(9):647-53. doi: 10.1111/j.1365-2362.2006.01700.x.
• [11] Mineralocorticoid receptor function in posttraumatic stress disorder after pretreatment with metyrapone. Biol Psychiatry. 2006 Oct 1;60(7):784-7. doi: 10.1016/j.biopsych.2006.01.014. Epub 2006 Mar 29.
• [12] Biochemical properties of human dehydrogenase/reductase (SDR family) member 7. Chem Biol Interact. 2014 Jan 25;207:52-7. doi: 10.1016/j.cbi.2013.11.003. Epub 2013 Nov 16.
• [13] Hydrocortisone enhances the barrier properties of HBMEC/ci, a brain microvascular endothelial cell line, through mesenchymal-to-endothelial transition-like effects. Fluids Barriers CNS. 2015 Mar 5;12:7. doi: 10.1186/s12987-015-0003-0. eCollection 2015.
• [14] Effect of cortisol on cell proliferation and the expression of lipoprotein lipase and vascular endothelial growth factor in a human osteosarcoma cell line. Cancer Chemother Pharmacol. 2008 Mar;61(3):471-9. doi: 10.1007/s00280-007-0492-x. Epub 2007 Jun 5.
• [15] Peripheral CLOCK regulates target-tissue glucocorticoid receptor transcriptional activity in a circadian fashion in man. PLoS One. 2011;6(9):e25612. doi: 10.1371/journal.pone.0025612. Epub 2011 Sep 28.
• [16] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [17] Oral and inhaled corticosteroids: differences in P-glycoprotein (ABCB1) mediated efflux. Toxicol Appl Pharmacol. 2012 May 1;260(3):294-302.
• [18] Regulation of the CYP3A4 gene by hydrocortisone and xenobiotics: role of the glucocorticoid and pregnane X receptors. Drug Metab Dispos. 2000 May;28(5):493-6.
• [19] CYP3A5 genotype is associated with elevated blood pressure. Pharmacogenet Genomics. 2005 Oct;15(10):737-41.
• [20] Steroid hydroxylation by human fetal CYP3A7 and human NADPH-cytochrome P450 reductase coexpressed in insect cells using baculovirus. Res Commun Mol Pathol Pharmacol. 1998 Apr;100(1):15-28.
• [21] Studies on the origin of circulating 18-hydroxycortisol and 18-oxocortisol in normal human subjects. J Clin Endocrinol Metab. 2004 Sep;89(9):4628-33.
• [22] Oral and inhaled corticosteroids: differences in P-glycoprotein (ABCB1) mediated efflux. Toxicol Appl Pharmacol. 2012 May 1;260(3):294-302. doi: 10.1016/j.taap.2012.03.008. Epub 2012 Mar 23.
• [23] Monomeric and oligomeric flavanols maintain the endogenous glucocorticoid response in human macrophages in pro-oxidant conditions in vitro. Chem Biol Interact. 2018 Aug 1;291:237-244.
• [24] Testosterone stimulates adipose tissue 11beta-hydroxysteroid dehydrogenase type 1 expression in a depot-specific manner in children. J Clin Endocrinol Metab. 2010 Jul;95(7):3300-8.
• [25] Ultradian cortisol pulsatility encodes a distinct, biologically important signal. PLoS One. 2011 Jan 18;6(1):e15766.
• [26] Towards a systematic analysis of human short-chain dehydrogenases/reductases (SDR): Ligand identification and structure-activity relationships. Chem Biol Interact. 2015 Jun 5;234:114-25.
• [27] Glucocorticoid-activation system mediated glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis programming alteration of adrenal dysfunction induced by prenatal caffeine exposure. Toxicol Lett. 2019 Mar 1;302:7-17.
• [28] Differential regulation of the human MRP2 and MRP3 gene expression by glucocorticoids. J Steroid Biochem Mol Biol. 2005 Aug;96(3-4):229-34. doi: 10.1016/j.jsbmb.2005.03.004.
• [29] Effect of hydrocortisone on the maturation of human foetal kidney explants in serum-free organ culture. Biochem Cell Biol. 1989 Feb-Mar;67(2-3):121-7. doi: 10.1139/o89-019.
• [30] Acute effects of hydrocortisone on plasma nitrate/nitrite activity and forearm vasodilator responsiveness in normal human subjects. Clin Exp Pharmacol Physiol. 2005 Mar;32(3):162-6. doi: 10.1111/j.1440-1681.2005.04173.x.
• [31] Stress doses of hydrocortisone reduce severe systemic inflammatory response syndrome and improve early outcome in a risk group of patients after cardiac surgery. Crit Care Med. 2003 Apr;31(4):1068-74. doi: 10.1097/01.CCM.0000059646.89546.98.
• [32] Experimental studies on cortisol-induced hypertension in humans. J Hum Hypertens. 1995 Jun;9(6):395-9.
• [33] Neuropeptide Y in cortisol-induced hypertension in male volunteers. Clin Exp Pharmacol Physiol. 1994 May;21(5):435-8. doi: 10.1111/j.1440-1681.1994.tb02538.x.
• [34] Deducing signaling pathways from parallel actions of arsenite and antimonite in human epidermal keratinocytes. Sci Rep. 2020 Feb 19;10(1):2890. doi: 10.1038/s41598-020-59577-0.
• [35] Regulation of messenger RNAs for the hydrophobic surfactant proteins in human lung. J Clin Invest. 1989 Apr;83(4):1191-7. doi: 10.1172/JCI114000.
• [36] Cell-based and cytokine-directed chemical screen to identify potential anti-multiple myeloma agents. Leuk Res. 2010 Jul;34(7):917-24. doi: 10.1016/j.leukres.2009.12.002. Epub 2010 Feb 8.
• [37] Tacrolimus ointment causes inflammatory dendritic epidermal cell depletion but no Langerhans cell apoptosis in patients with atopic dermatitis. J Allergy Clin Immunol. 2004 Jul;114(1):137-43. doi: 10.1016/j.jaci.2004.03.021.
• [38] P2Y receptor regulation of sodium transport in human mammary epithelial cells. Am J Physiol Cell Physiol. 2007 Nov;293(5):C1472-80. doi: 10.1152/ajpcell.00068.2007. Epub 2007 Aug 22.
• [39] Prenatal caffeine exposure increases the susceptibility to non-alcoholic fatty liver disease in female offspring rats via activation of GR-C/EBP-SIRT1 pathway. Toxicology. 2019 Apr 1;417:23-34. doi: 10.1016/j.tox.2019.02.008. Epub 2019 Feb 15.
• [40] Intergenerational genetic programming mechanism and sex differences of the adrenal corticosterone synthesis dysfunction in offspring induced by prenatal ethanol exposure. Toxicol Lett. 2021 Oct 15;351:78-88. doi: 10.1016/j.toxlet.2021.08.007. Epub 2021 Aug 25.
• [41] Relation of oxytocin to psychological stress responses and hypothalamic-pituitary-adrenocortical axis activity in older women. Psychosom Med. 2006 Mar-Apr;68(2):238-45. doi: 10.1097/01.psy.0000203242.95990.74.
• [42] Human and murine steroid 5-reductases (AKR1D1 and AKR1D4): insights into the role of the catalytic glutamic acid. Chem Biol Interact. 2019 May 25;305:163-170. doi: 10.1016/j.cbi.2019.03.025. Epub 2019 Mar 28.
• [43] Overexpression of RbAp46 facilitates stress-induced apoptosis and suppresses tumorigenicity of neoplastigenic breast epithelial cells. Int J Cancer. 2003 Jul 20;105(6):762-8. doi: 10.1002/ijc.11148.
• [44] Stimulation of progesterone, estradiol and cortisol in trophoblast tumor bewo cells by glycodelin A N-glycans. Anticancer Res. 2007 Jul-Aug;27(4A):2101-8.
• [45] Melatonin exerts direct inhibitory actions on ACTH responses in the human adrenal gland. Horm Metab Res. 2011 May;43(5):337-42. doi: 10.1055/s-0031-1271693. Epub 2011 Feb 17.
• [46] Low estriol levels in the maternal triple-marker screen as a predictor of isolated adrenocorticotropic hormone deficiency caused by a new mutation in the TPIT gene. Pediatrics. 2006 Feb;117(2):e322-7. doi: 10.1542/peds.2005-1973. Epub 2006 Jan 3.