Details of the Drug Combination

General Information of Drug Combination (ID: DCPXP5D)

• Drug Combination Name: Leuprolide + Flutamide
• Indication: Prostatic Neoplasms; Status: Phase 1 [1]
• Component Drugs:
  Leuprolide (DM5XPIJ): Small molecular drug
  Flutamide (DMK0O7U): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Leuprolide

Disease Entry	ICD 11	Status	REF
Plasma cell myeloma	2A83.1	Approved	[2]
Prostate cancer	2C82.0	Approved	[3]
Endometriosis	GA10	Investigative	[2]

Leuprolide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Leutinizing-hormone-releasing hormone (GNRH1)	TT0ID4A	GON1_HUMAN	Activator	[5]

Leuprolide Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Thyroxine-binding globulin (SERPINA7)	OTUYVTSU	THBG_HUMAN	Increases ADR	[6]
Protein bric-a-brac 2 (bab2)	OTNNK0KI	BAB2_DROME	Increases ADR	[6]

Indication(s) of Flutamide

Disease Entry	ICD 11	Status	REF
Prostate cancer	2C82.0	Approved	[4]

Flutamide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Androgen receptor (AR)	TTS64P2	ANDR_HUMAN	Antagonist	[7]

Flutamide Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 1 (ABCC1)	DTSYQGK	MRP1_HUMAN	Substrate	[8]

Flutamide Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[10]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[11]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[9]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[9]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[11]

Flutamide Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases Response To Substance	[12]
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[13]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[14]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[13]
Protein S100-A8 (S100A8)	OTVMOB3F	S10A8_HUMAN	Increases Expression	[15]
Protein S100-A9 (S100A9)	OTOARHCS	S10A9_HUMAN	Increases Expression	[15]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[14]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[13]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[13]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Activity	[16]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Affects Localization	[17]
Tumor necrosis factor-inducible gene 6 protein (TNFAIP6)	OT1SLUZH	TSG6_HUMAN	Increases Expression	[13]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[13]
NACHT, LRR and PYD domains-containing protein 3 (NLRP3)	OTZM6MHU	NLRP3_HUMAN	Increases Expression	[15]
Arylacetamide deacetylase (AADAC)	OT8VACT2	AAAD_HUMAN	Increases Hydrolysis	[18]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Prostate Cancer	DCYQ0KN	N. A.	Phase 1	[19]

References

• [1] ClinicalTrials.gov (NCT00817739) Intermittent Hormonal Therapy With Leuprorelin and Flutamide in the Treatment of Stage D2 or TxNxM1b,c
• [2] Leuprolide 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: 1175).
• [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: 6943).
• [5] Increased risk of metabolic syndrome, diabetes mellitus, and cardiovascular disease in men receiving androgen deprivation therapy for prostate cancer. Pharmacotherapy. 2008 Dec;28(12):1511-22.
• [6] 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.
• [7] Androgen receptor as a target in androgen-independent prostate cancer. Urology. 2002 Sep;60(3 Suppl 1):132-8; discussion 138-9.
• [8] The multidrug resistance-associated protein 1 transports methoxychlor and protects the seminiferous epithelium from injury. Toxicol Lett. 2003 Apr 30;142(1-2):61-70.
• [9] Identification of a novel glutathione conjugate of flutamide in incubations with human liver microsomes. Drug Metab Dispos. 2007 Jul;35(7):1081-8.
• [10] Metabolism of the antiandrogenic drug (Flutamide) by human CYP1A2. Drug Metab Dispos. 1997 Nov;25(11):1298-303.
• [11] Human CYP1B1 and anticancer agent metabolism: mechanism for tumor-specific drug inactivation? J Pharmacol Exp Ther. 2001 Feb;296(2):537-41.
• [12] Customised in vitro model to detect human metabolism-dependent idiosyncratic drug-induced liver injury. Arch Toxicol. 2018 Jan;92(1):383-399. doi: 10.1007/s00204-017-2036-4. Epub 2017 Jul 31.
• [13] 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.
• [14] PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line. Cancer Chemother Pharmacol. 2010 Sep;66(4):765-71. doi: 10.1007/s00280-009-1221-4. Epub 2009 Dec 30.
• [15] Prediction of drug-induced liver injury using keratinocytes. J Appl Toxicol. 2017 Jul;37(7):863-872. doi: 10.1002/jat.3435. Epub 2017 Jan 31.
• [16] 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.
• [17] Proliferative and androgenic effects of indirubin derivatives in LNCaP human prostate cancer cells at sub-apoptotic concentrations. Chem Biol Interact. 2011 Feb 1;189(3):177-85. doi: 10.1016/j.cbi.2010.11.008. Epub 2010 Nov 25.
• [18] Species differences in tissue distribution and enzyme activities of arylacetamide deacetylase in human, rat, and mouse. Drug Metab Dispos. 2012 Apr;40(4):671-9. doi: 10.1124/dmd.111.043067. Epub 2011 Dec 29.
• [19] ClinicalTrials.gov (NCT00003645) Randomized Trial of Adjuvant Hormonal Therapy in Surgically Treated Prostate Cancer Patients at High Risk for Recurrence