Details of the Drug Combination

General Information of Drug Combination (ID: DCJK1VN)

• Drug Combination Name: Fludrocortisone + Bromocriptine
• Indication: Ovarian Hyperstimulation Syndrome; Status: Phase 2 [1]
• Component Drugs:
  Fludrocortisone (DMUDIR8): Small molecular drug
  Bromocriptine (DMVE3TK): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Fludrocortisone

Disease Entry	ICD 11	Status	REF
Addison disease	5A74.0	Approved	[2]
Cerebral salt-wasting syndrome	5C72	Approved	[3]
Congenital adrenal hyperplasia	5A71.01	Approved	[2]

Fludrocortisone Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Androgen receptor (AR)	TTS64P2	ANDR_HUMAN	Inhibitor	[7]
Mineralocorticoid receptor (MR)	TT26PHO	MCR_HUMAN	Agonist	[8]

Fludrocortisone Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]

Fludrocortisone Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Decreases Expression	[10]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Decreases Expression	[10]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[10]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[10]
Prostate-specific antigen (KLK3)	OTFGSBFJ	KLK3_HUMAN	Increases Expression	[11]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[10]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[10]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Increases Expression	[6]
C-C motif chemokine 4 (CCL4)	OT6B8P25	CCL4_HUMAN	Increases Expression	[6]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Expression	[6]
Bone morphogenetic protein 6 (BMP6)	OT9WN536	BMP6_HUMAN	Decreases Expression	[10]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[10]
Tumor necrosis factor-inducible gene 6 protein (TNFAIP6)	OT1SLUZH	TSG6_HUMAN	Decreases Expression	[10]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[10]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Decreases Expression	[10]

Indication(s) of Bromocriptine

Disease Entry	ICD 11	Status	REF
Acromegaly	5A60.0	Approved	[4]
Hyperprolactinaemia	5A60.1	Approved	[4]
Parkinson disease	8A00.0	Approved	[5]
Postencephalitic Parkinson disease	N.A.	Approved	[4]

Bromocriptine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dopamine D2 receptor (D2R)	TTEX248	DRD2_HUMAN	Agonist	[12]

Bromocriptine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]

Bromocriptine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[14]

Bromocriptine Interacts with 14 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Affects Binding	[15]
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Increases Response To Substance	[16]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Increases Expression	[17]
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Increases Expression	[18]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Increases Expression	[18]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Decreases Expression	[19]
Somatotropin (GH1)	OT92RTRD	SOMA_HUMAN	Decreases Expression	[20]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Decreases Expression	[21]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[22]
Dopamine beta-hydroxylase (DBH)	OTC6I2SP	DOPO_HUMAN	Decreases Activity	[23]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[24]
Cyclic AMP-dependent transcription factor ATF-3 (ATF3)	OTC1UOHP	ATF3_HUMAN	Increases Expression	[24]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Increases Localization	[24]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[22]

References

• [1] ClinicalTrials.gov (NCT04351126) Management of Ovarian Hyperstimulation Syndrome as a State of Defective Mineralocorticoid Response
• [2] Fludrocortisone 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: 2873).
• [4] Bromocriptine FDA Label
• [5] 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: 35).
• [6] 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.
• [7] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [8] Mineralocorticoid receptor-mediated inhibition of the hypothalamic-pituitary-adrenal axis in aged humans. J Gerontol A Biol Sci Med Sci. 2003 Oct;58(10):B900-5.
• [9] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [10] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [11] A glucocorticoid-responsive mutant androgen receptor exhibits unique ligand specificity: therapeutic implications for androgen-independent prostate cancer. Endocrinology. 2002 May;143(5):1889-900. doi: 10.1210/endo.143.5.8778.
• [12] Silymarin BIO-C, an extract from Silybum marianum fruits, induces hyperprolactinemia in intact female rats. Phytomedicine. 2009 Sep;16(9):839-44.
• [13] Improving the prediction of the brain disposition for orally administered drugs using BDDCS. Adv Drug Deliv Rev. 2012 Jan;64(1):95-109.
• [14] Kinetics of dithionite-dependent reduction of cytochrome P450 3A4: heterogeneity of the enzyme caused by its oligomerization. Biochemistry. 2005 Oct 25;44(42):13902-13.
• [15] Mechanism of interactions of alpha-naphthoflavone with cytochrome P450 3A4 explored with an engineered enzyme bearing a fluorescent probe. Biochemistry. 2007 Jan 9;46(1):106-19. doi: 10.1021/bi061944p.
• [16] Imaging gene-substance interactions: the effect of the DRD2 TaqIA polymorphism and the dopamine agonist bromocriptine on the brain activation during the anticipation of reward. Neurosci Lett. 2006 Sep 25;405(3):196-201. doi: 10.1016/j.neulet.2006.07.030. Epub 2006 Aug 8.
• [17] Bromocriptine inhibits pro-opiomelanocortin mRNA and ACTH precursor secretion in small cell lung cancer cell lines. J Clin Invest. 1992 Sep;90(3):705-10. doi: 10.1172/JCI115941.
• [18] Resolution of hyperprolactinaemia after bromocriptine-induced pregnancy. Lancet. 1979 Apr 7;1(8119):784-5. doi: 10.1016/s0140-6736(79)91247-9.
• [19] Long-term follow-up of prolactinomas: normoprolactinemia after bromocriptine withdrawal. J Clin Endocrinol Metab. 2002 Aug;87(8):3578-82. doi: 10.1210/jcem.87.8.8722.
• [20] Improvement of congestive heart failure after octreotide and transsphenoidal surgery in a patient with acromegaly. Intern Med. 2009;48(9):697-700. doi: 10.2169/internalmedicine.48.1537. Epub 2009 May 1.
• [21] Activation of dopamine D2 receptors simultaneously ameliorates various metabolic features of obese women. Am J Physiol Endocrinol Metab. 2006 Nov;291(5):E1038-43. doi: 10.1152/ajpendo.00567.2005. Epub 2006 Jun 27.
• [22] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [23] Plasma dopamine beta hydroxylase (D.B.H.) activity in Parkinsonian patients under L-dopa, and 2-bromo-alpha-ergocriptine loading. J Neural Transm. 1979;46(1):71-8. doi: 10.1007/BF01243430.
• [24] Bromocriptine methylate suppresses glial inflammation and moderates disease progression in a mouse model of amyotrophic lateral sclerosis. Exp Neurol. 2011 Nov;232(1):41-52. doi: 10.1016/j.expneurol.2011.08.001. Epub 2011 Aug 16.