Details of the Drug Combination

General Information of Drug Combination (ID: DCGOLRW)

• Drug Combination Name: Methimazole + Mycophenolate mofetil
• Indication: Graves' Disease; Status: Phase 2 [1]
• Component Drugs:
  Methimazole (DM25FL8): Small molecular drug
  Mycophenolate mofetil (DMPQAGE): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Methimazole

Disease Entry	ICD 11	Status	REF
Hyperthyroidism	5A02	Approved	[2]

Methimazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Thyroid peroxidase (TPO)	TT52XDZ	PERT_HUMAN	Inhibitor	[8]

Methimazole Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Dimethylaniline oxidase 2 (FMO2)	DEIASEZ	FMO2_HUMAN	Metabolism	[9]

Methimazole Interacts with 43 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Expression	[10]
Serum paraoxonase/arylesterase 1 (PON1)	OTD0Z2XO	PON1_HUMAN	Increases Activity	[11]
T-box transcription factor TBX3 (TBX3)	OTM64N7K	TBX3_HUMAN	Increases Expression	[7]
Trans-Golgi network integral membrane protein 2 (TGOLN2)	OTM647IV	TGON2_HUMAN	Increases Expression	[7]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Increases Expression	[12]
Haptoglobin (HP)	OTGUGAF9	HPT_HUMAN	Increases Expression	[12]
Thyrotropin subunit beta (TSHB)	OTFDI39D	TSHB_HUMAN	Increases Expression	[13]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Decreases Expression	[14]
Alpha-fetoprotein (AFP)	OT9GG3ZI	FETA_HUMAN	Increases Expression	[14]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Decreases Expression	[14]
Insulin-like growth factor I (IGF1)	OTIIZR61	IGF1_HUMAN	Decreases Expression	[14]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Expression	[12]
Thyroid peroxidase (TPO)	OTJJLL20	PERT_HUMAN	Decreases Activity	[15]
Insulin-like growth factor 1 receptor (IGF1R)	OTXJIF13	IGF1R_HUMAN	Decreases Expression	[14]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[12]
Microsomal glutathione S-transferase 1 (MGST1)	OTGN1KVZ	MGST1_HUMAN	Increases Expression	[12]
Proliferating cell nuclear antigen (PCNA)	OTHZ1RIA	PCNA_HUMAN	Decreases Expression	[14]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[7]
Thyrotropin receptor (TSHR)	OT0BC8LB	TSHR_HUMAN	Decreases Expression	[16]
Galectin-3 (LGALS3)	OTYQT0ZI	LEG3_HUMAN	Increases Expression	[12]
Integrin beta-5 (ITGB5)	OT21MF51	ITB5_HUMAN	Increases Expression	[7]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[14]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[14]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Decreases Phosphorylation	[14]
RAC-beta serine/threonine-protein kinase (AKT2)	OTBB632K	AKT2_HUMAN	Decreases Expression	[14]
Hepatocyte nuclear factor 4-alpha (HNF4A)	OTY1TOAB	HNF4A_HUMAN	Increases Expression	[14]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Expression	[14]
Glutamate--cysteine ligase catalytic subunit (GCLC)	OTESDI4D	GSH1_HUMAN	Increases Expression	[12]
Fatty acid synthase (FASN)	OTFII9KG	FAS_HUMAN	Decreases Expression	[14]
Type I iodothyronine deiodinase (DIO1)	OTFYLYJ0	IOD1_HUMAN	Increases Expression	[16]
Hepcidin (HAMP)	OT607RBL	HEPC_HUMAN	Decreases Expression	[12]
Low-density lipoprotein receptor-related protein 2 (LRP2)	OTZ6W681	LRP2_HUMAN	Increases Expression	[16]
DNA-binding protein inhibitor ID-2 (ID2)	OT0U1D53	ID2_HUMAN	Increases Expression	[7]
DNA-binding protein inhibitor ID-3 (ID3)	OTUULW5Z	ID3_HUMAN	Increases Expression	[7]
Krueppel-like factor 9 (KLF9)	OTBFEJRQ	KLF9_HUMAN	Increases Expression	[7]
Consortin (CNST)	OTOUCB98	CNST_HUMAN	Increases Expression	[7]
Sodium/iodide cotransporter (SLC5A5)	OTU7E9G7	SC5A5_HUMAN	Increases Expression	[16]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Decreases Expression	[17]
PTB domain-containing engulfment adapter protein 1 (GULP1)	OT1WMVDH	GULP1_HUMAN	Increases Expression	[7]
Flavin-containing monooxygenase 3 (FMO3)	OT1G2EV3	FMO3_HUMAN	Increases Metabolism	[18]
Cytochrome P450 2A6 (CYP2A6)	OT52TWG3	CP2A6_HUMAN	Increases Metabolism	[19]
Flavin-containing monooxygenase 1 (FMO1)	OTTHSQKP	FMO1_HUMAN	Increases Oxidation	[20]
Flavin-containing monooxygenase 2 (FMO2)	OTUJUL9S	FMO2_HUMAN	Decreases Oxidation	[21]

Indication(s) of Mycophenolate mofetil

Disease Entry	ICD 11	Status	REF
Hepatosplenic T-cell lymphoma	N.A.	Approved	[3]
Interstitial cystitis	GC00.3	Approved	[3]
Large granular lymphocytic leukemia	2A90.1	Approved	[3]
Lupus nephritis	4A40.0Y	Approved	[3]
MALT lymphoma	N.A.	Approved	[3]
Myeloid leukaemia	2B33.1	Approved	[3]
Myeloproliferative neoplasm	2A20	Approved	[3]
Nodal marginal zone lymphoma	2A85.0	Approved	[3]
Organ transplant rejection	NE84	Approved	[4]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	N.A.	Approved	[3]
Recurrent adult burkitt lymphoma	2A85.6	Approved	[3]
Small intestine lymphoma	N.A.	Approved	[3]
Splenic marginal zone lymphoma	N.A.	Approved	[3]
Systemic lupus erythematosus	4A40.0	Approved	[3]
Testicular lymphoma	N.A.	Approved	[3]
Pemphigus vulgaris	EB40	Phase 3	[4]
Classic Hodgkin lymphoma	N.A.	Investigative	[3]
Immune System disease	4A01-4B41	Investigative	[5]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[6]

Mycophenolate mofetil Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Prostaglandin E2 receptor EP2 (PTGER2)	TT1ZAVI	PE2R2_HUMAN	Modulator	[5]
Inosine-5'-monophosphate dehydrogenase 2 (IMPDH2)	TTTB4UP	IMDH2_HUMAN	Inhibitor	[22]

Mycophenolate mofetil Interacts with 5 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[23]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[24]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[24]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[23]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[23]

Mycophenolate mofetil Interacts with 8 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[25]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[26]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[25]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[25]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[25]
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_HUMAN	Metabolism	[27]
UDP-glucuronosyltransferase 1A6 (UGT1A6)	DESD26P	UD16_HUMAN	Metabolism	[26]
UDP-glucuronosyltransferase 1A10 (UGT1A10)	DEL5N6Y	UD110_HUMAN	Metabolism	[28]

References

• [1] ClinicalTrials.gov (NCT06068179) Graves' Disease Remission Study: MycoMeth Combo
• [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: 6649).
• [3] Mycophenolate mofetil 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: 6831).
• [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. (Target id: 341).
• [6] High-Throughput Screening and Identification of Potent Broad-Spectrum Inhibitors of Coronaviruses. J Virol. 2019 May 29;93(12). pii: e00023-19.
• [7] Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
• [8] Diagnosis and treatment of thyrotoxicosis in childhood. A European questionnaire study. Eur J Endocrinol. 1994 Nov;131(5):467-73.
• [9] Drug metabolism by flavin-containing monooxygenases of human and mouse. Expert Opin Drug Metab Toxicol. 2017 Feb;13(2):167-181.
• [10] Hepatocellular peroxisomes in human alcoholic and drug-induced hepatitis: a quantitative study. Hepatology. 1991 Nov;14(5):811-7.
• [11] Serum paraoxonase activity before and after treatment of thyrotoxicosis. Clin Endocrinol (Oxf). 2004 Jan;60(1):75-80.
• [12] Blood cell oxidative stress precedes hemolysis in whole blood-liver slice co-cultures of rat, dog, and human tissues. Toxicol Appl Pharmacol. 2010 May 1;244(3):354-65. doi: 10.1016/j.taap.2010.01.017. Epub 2010 Feb 6.
• [13] Effect of 1 alpha-hydroxyvitamin D3 on serum levels of thyroid hormones in hyperthyroid patients with untreated Graves' disease. Metabolism. 1997 Oct;46(10):1184-8. doi: 10.1016/s0026-0495(97)90214-6.
• [14] Low-expressional IGF1 mediated methimazole-induced liver developmental toxicity in fetal mice. Toxicology. 2018 Sep 1;408:70-79. doi: 10.1016/j.tox.2018.07.004. Epub 2018 Jul 7.
• [15] Identification of classifiers for increase or decrease of thyroid peroxidase activity in the FTC-238/hTPO recombinant cell line. Environ Sci Technol. 2011 Sep 15;45(18):7906-14. doi: 10.1021/es200475k. Epub 2011 Aug 24.
• [16] Thyroid organotypic rat and human cultures used to investigate drug effects on thyroid function, hormone synthesis and release pathways. Toxicol Appl Pharmacol. 2012 Apr 1;260(1):81-8. doi: 10.1016/j.taap.2012.01.029. Epub 2012 Feb 8.
• [17] Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.
• [18] Identification and functional analysis of common human flavin-containing monooxygenase 3 genetic variants. J Pharmacol Exp Ther. 2007 Jan;320(1):266-73. doi: 10.1124/jpet.106.112268. Epub 2006 Oct 18.
• [19] Role of CYP2A6 in Methimazole Bioactivation and Hepatotoxicity. Chem Res Toxicol. 2021 Dec 20;34(12):2534-2539. doi: 10.1021/acs.chemrestox.1c00300. Epub 2021 Nov 17.
• [20] Evaluation of xenobiotic N- and S-oxidation by variant flavin-containing monooxygenase 1 (FMO1) enzymes. Toxicol Sci. 2004 Apr;78(2):196-203.
• [21] Haplotype and functional analysis of four flavin-containing monooxygenase isoform 2 (FMO2) polymorphisms in Hispanics. Pharmacogenet Genomics. 2005 Apr;15(4):245-56. doi: 10.1097/01213011-200504000-00008.
• [22] Clinical pipeline report, company report or official report of Roche (2009).
• [23] Influence of SLCO1B1, 1B3, 2B1 and ABCC2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients. Eur J Clin Pharmacol. 2007 Dec;63(12):1161-9.
• [24] Influence of drug transporters and UGT polymorphisms on pharmacokinetics of phenolic glucuronide metabolite of mycophenolic acid in Japanese renal transplant recipients. Ther Drug Monit. 2008 Oct;30(5):559-64.
• [25] PharmGKB summary: mycophenolic acid pathway. Pharmacogenet Genomics. 2014 Jan;24(1):73-9.
• [26] Characterization of rat intestinal microsomal UDP-glucuronosyltransferase activity toward mycophenolic acid. Drug Metab Dispos. 2006 Sep;34(9):1632-9.
• [27] The evolution of population pharmacokinetic models to describe the enterohepatic recycling of mycophenolic acid in solid organ transplantation and autoimmune disease. Clin Pharmacokinet. 2011 Jan;50(1):1-24.
• [28] [Pharmacology of mycophenolate mofetil: recent data and clinical consequences]. Nephrologie. 2001;22(7):331-7.