Details of the Drug Combination

General Information of Drug Combination (ID: DCWSC1S)

• Drug Combination Name: Budesonide + Mycophenolate mofetil
• Indication: Acute Cellular Graft Rejection; Status: Phase 4 [1]
• Component Drugs:
  Budesonide (DMJIBAW): Small molecular drug
  Mycophenolate mofetil (DMPQAGE): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Budesonide

Disease Entry	ICD 11	Status	REF
Allergic rhinitis	CA08.0	Approved	[2]
Asthma	CA23	Approved	[3]
Crohn disease	DD70	Approved	[2]
Inflammatory bowel disease	DD72	Approved	[2]
Radiation proctitis	N.A.	Approved	[2]
Ulcerative colitis	DD71	Approved	[2]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[4]

Budesonide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Glucocorticoid receptor (NR3C1)	TTYRL6O	GCR_HUMAN	Antagonist	[10]

Budesonide Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Sulfotransferase 1A1 (SULT1A1)	DEYWLRK	ST1A1_HUMAN	Metabolism	[12]

Budesonide Interacts with 28 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[13]
Metallothionein-2 (MT2A)	OTHOACHD	MT2_HUMAN	Increases Expression	[14]
Glucocorticoid receptor (NR3C1)	OTCI2YDI	GCR_HUMAN	Decreases Expression	[14]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Increases Expression	[15]
Cytosolic phospholipase A2 (PLA2G4A)	OTE70SOT	PA24A_HUMAN	Decreases Activity	[16]
Organic solute transporter subunit alpha (SLC51A)	OTDJRZ0P	OSTA_HUMAN	Increases Expression	[13]
Organic solute transporter subunit beta (SLC51B)	OT4WYPSR	OSTB_HUMAN	Increases Expression	[13]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[17]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[18]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[19]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Decreases Secretion	[20]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Secretion	[20]
Lactotransferrin (LTF)	OT8JWCZ0	TRFL_HUMAN	Decreases Secretion	[21]
Osteocalcin (BGLAP)	OTK1YLWQ	OSTCN_HUMAN	Decreases Expression	[22]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Decreases Secretion	[23]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Decreases Expression	[24]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[25]
Mineralocorticoid receptor (NR3C2)	OT0F2V2Z	MCR_HUMAN	Increases Activity	[26]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Increases Expression	[9]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[24]
Eosinophil cationic protein (RNASE3)	OTVE2XD1	ECP_HUMAN	Decreases Expression	[27]
C-C motif chemokine 4 (CCL4)	OT6B8P25	CCL4_HUMAN	Increases Expression	[9]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Expression	[9]
Interleukin-4 receptor subunit alpha (IL4R)	OTTXOTCW	IL4RA_HUMAN	Decreases Expression	[28]
Interleukin-13 (IL13)	OTI4YS3Y	IL13_HUMAN	Increases Activity	[29]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[30]
C-C motif chemokine 17 (CCL17)	OTIKW21L	CCL17_HUMAN	Decreases Expression	[28]
T-box transcription factor TBX21 (TBX21)	OT3UK5KE	TBX21_HUMAN	Increases Response	[31]

Indication(s) of Mycophenolate mofetil

Disease Entry	ICD 11	Status	REF
Hepatosplenic T-cell lymphoma	N.A.	Approved	[5]
Interstitial cystitis	GC00.3	Approved	[5]
Large granular lymphocytic leukemia	2A90.1	Approved	[5]
Lupus nephritis	4A40.0Y	Approved	[5]
MALT lymphoma	N.A.	Approved	[5]
Myeloid leukaemia	2B33.1	Approved	[5]
Myeloproliferative neoplasm	2A20	Approved	[5]
Nodal marginal zone lymphoma	2A85.0	Approved	[5]
Organ transplant rejection	NE84	Approved	[6]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	N.A.	Approved	[5]
Recurrent adult burkitt lymphoma	2A85.6	Approved	[5]
Small intestine lymphoma	N.A.	Approved	[5]
Splenic marginal zone lymphoma	N.A.	Approved	[5]
Systemic lupus erythematosus	4A40.0	Approved	[5]
Testicular lymphoma	N.A.	Approved	[5]
Pemphigus vulgaris	EB40	Phase 3	[6]
Classic Hodgkin lymphoma	N.A.	Investigative	[5]
Immune System disease	4A01-4B41	Investigative	[7]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[8]

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	[7]
Inosine-5'-monophosphate dehydrogenase 2 (IMPDH2)	TTTB4UP	IMDH2_HUMAN	Inhibitor	[32]

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	[33]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[34]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[34]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[33]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[33]

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	[35]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[36]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[35]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[35]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[35]
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_HUMAN	Metabolism	[37]
UDP-glucuronosyltransferase 1A6 (UGT1A6)	DESD26P	UD16_HUMAN	Metabolism	[36]
UDP-glucuronosyltransferase 1A10 (UGT1A10)	DEL5N6Y	UD110_HUMAN	Metabolism	[38]

References

• [1] ClinicalTrials.gov (NCT03315052) Budesonide for Immunosuppression After Liver Transplantation to Reduce Side Effects
• [2] Budesonide 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: 7434).
• [4] Inhaled Corticosteroid Treatment of COVID19 Patients With Pneumonia
• [5] Mycophenolate mofetil 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: 6831).
• [7] 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).
• [8] High-Throughput Screening and Identification of Potent Broad-Spectrum Inhibitors of Coronaviruses. J Virol. 2019 May 29;93(12). pii: e00023-19.
• [9] 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.
• [10] PXR-mediated induction of human CYP3A4 and mouse Cyp3a11 by the glucocorticoid budesonide. Eur J Pharm Sci. 2009 Mar 2;36(4-5):565-71.
• [11] No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis. Hepatology. 2005 Mar;41(3):595-602.
• [12] Sulfation of budesonide by human cytosolic sulfotransferase, dehydroepiandrosterone-sulfotransferase (DHEA-ST). Drug Metab Dispos. 2002 May;30(5):582-5.
• [13] Expression and regulation of the bile acid transporter, OSTalpha-OSTbeta in rat and human intestine and liver. Biopharm Drug Dispos. 2009 Jul;30(5):241-58.
• [14] Interaction between glucocorticoids and beta2-agonists: alpha and beta glucocorticoid-receptor mRNA expression in human bronchial epithelial cells. Biochem Pharmacol. 1998 Dec 15;56(12):1561-9.
• [15] Regulation of CYP3A5 by glucocorticoids and cigarette smoke in human lung-derived cells. J Pharmacol Exp Ther. 2003 Feb;304(2):745-52.
• [16] Comparison of in vitro-activity of commonly used topical glucocorticoids on cytokine- and phospholipase inhibition. Eur J Med Res. 2004 Aug 31;9(8):383-90.
• [17] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [18] Screening of a chemical library reveals novel PXR-activating pharmacologic compounds. Toxicol Lett. 2015 Jan 5;232(1):193-202. doi: 10.1016/j.toxlet.2014.10.009. Epub 2014 Oct 16.
• [19] Novel sulfhydryl-reactive compounds orazipone and OR-1958 inhibit cytokine production and histamine release in rat and human mast cells. Int Immunopharmacol. 2005 Jan;5(1):177-84. doi: 10.1016/j.intimp.2004.07.020.
• [20] Evaluation of the inhibitory effects of budesonide on the mitogen-induced or the allergen-induced activation of blood mononuclear cells isolated from asthmatic patients. Ann Allergy Asthma Immunol. 1995 Jul;75(1):33-40.
• [21] Effects of topical glucocorticoids on in vitro lactoferrin glandular secretion: comparison between human upper and lower airways. J Allergy Clin Immunol. 2000 Dec;106(6):1053-62. doi: 10.1067/mai.2000.110476.
• [22] The effects of inhaled glucocorticoids on bone mass and biochemical markers of bone homeostasis: a 1-year study of beclomethasone versus budesonide. Neth J Med. 1997 Jun;50(6):233-7. doi: 10.1016/s0300-2977(96)00081-2.
• [23] Inhibition of GM-CSF secretion by topical corticosteroids and nedocromil sodium. A comparison study using nasal polyp epithelial cells. Respir Med. 2000 May;94(5):428-31. doi: 10.1053/rmed.1999.0756.
• [24] A randomized phase IIb trial of pulmicort turbuhaler (budesonide) in people with dysplasia of the bronchial epithelium. Clin Cancer Res. 2004 Oct 1;10(19):6502-11. doi: 10.1158/1078-0432.CCR-04-0686.
• [25] 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.
• [26] Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties. Eur J Endocrinol. 2004 Sep;151(3):397-406. doi: 10.1530/eje.0.1510397.
• [27] Effects of different anti-asthmatic agents on induced sputum and eosinophil cationic protein in mild asthmatics. Respirology. 2004 Nov;9(4):514-20. doi: 10.1111/j.1440-1843.2004.00631.x.
• [28] Effect of inhaled corticosteroid on an immunoreactive thymus and activation-regulated chemokine expression in the bronchial biopsies from asthmatics. Allergy. 2005 Mar;60(3):317-22. doi: 10.1111/j.1398-9995.2005.00694.x.
• [29] [Effects of beclomethasone dipropionate and budesonide on interleukin-13 induced cytokine release, proliferation and differentiation of the human lung fibroblasts]. Zhonghua Jie He He Hu Xi Za Zhi. 2007 Aug;30(8):599-604.
• [30] Apoptosis of airway epithelial cells induced by corticosteroids. Am J Respir Crit Care Med. 2001 Nov 15;164(10 Pt 1):1939-47. doi: 10.1164/ajrccm.164.10.2103013.
• [31] TBX21: a functional variant predicts improvement in asthma with the use of inhaled corticosteroids. Proc Natl Acad Sci U S A. 2004 Dec 28;101(52):18099-104. doi: 10.1073/pnas.0408532102. Epub 2004 Dec 16.
• [32] Clinical pipeline report, company report or official report of Roche (2009).
• [33] 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.
• [34] 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.
• [35] PharmGKB summary: mycophenolic acid pathway. Pharmacogenet Genomics. 2014 Jan;24(1):73-9.
• [36] Characterization of rat intestinal microsomal UDP-glucuronosyltransferase activity toward mycophenolic acid. Drug Metab Dispos. 2006 Sep;34(9):1632-9.
• [37] 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.
• [38] [Pharmacology of mycophenolate mofetil: recent data and clinical consequences]. Nephrologie. 2001;22(7):331-7.