Details of the Drug Combination

General Information of Drug Combination (ID: DCLJ519)

• Drug Combination Name: Rolapitant + Sulfasalazine
• Indication: Chemotherapy-induced Nausea and Vomiting; Status: Phase 1 [1]
• Component Drugs:
  Rolapitant (DM8XP26): Small molecular drug
  Sulfasalazine (DMICA9H): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Rolapitant

Disease Entry	ICD 11	Status	REF
Chemotherapy-induced nausea	MD90	Approved	[2]

Rolapitant Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Substance-P receptor (TACR1)	TTZPO1L	NK1R_HUMAN	Antagonist	[6]

Rolapitant Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]

Indication(s) of Sulfasalazine

Disease Entry	ICD 11	Status	REF
Irritable bowel syndrome	DD91.0	Approved	[3]
Rheumatoid arthritis	FA20	Approved	[4]
Ulcerative colitis	DD71	Approved	[5]

Sulfasalazine Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
ATP-binding cassette transporter G2 (ABCG2)	TTIMJ02	ABCG2_HUMAN	Inhibitor	[10]
Nuclear factor NF-kappa-B (NFKB)	TTSXVID	NFKB1_HUMAN; NFKB2_HUMAN; TF65_HUMAN; RELB_HUMAN; REL_HUMAN	Activator	[11]

Sulfasalazine Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[12]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[13]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[14]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[15]

Sulfasalazine Interacts with 12 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[16]
Azoreductase (azoR)	DE5CAX1	A0A074IU04_STRSL	Metabolism	[17]
Azoreductase (azoR)	DEGTKHL	T0VG26_9ENTE	Metabolism	[18]
Azoreductase (azoR)	DE3UF6Z	A0A0P0ETC6_BACT4	Metabolism	[18]
Azoreductase (azoR)	DE6GHJ5	A0A0P0ETC6_BACT4	Metabolism	[18]
Azoreductase (azoR)	DEEISQ2	AZOR_ENTFA	Metabolism	[17]
Azoreductase (azoR)	DEI2PC5	AZOR_CLOP1	Metabolism	[17]
Azoreductase (azoR)	DETEMAH	A0A349MYB4_9LACO	Metabolism	[18]
Azoreductase (azoR)	DEM1BHT	A0A132Z973_ENTFC	Metabolism	[17]
Azoreductase (azoR)	DEIKZOU	A0A0P0ETC6_BACT4	Metabolism	[19]
Azoreductase (azoR)	DENLBG3	A0A0P0ETC6_BACT4	Metabolism	[17]
Azoreductase (azoR)	DEIHK8V	A0A349MYB4_9LACO	Metabolism	[17]

Sulfasalazine Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Decreases Methylation	[20]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Decreases Expression	[8]
Tumor necrosis factor receptor superfamily member 11B (TNFRSF11B)	OTQ4W7MT	TR11B_HUMAN	Increases Secretion	[21]
Tumor necrosis factor ligand superfamily member 11 (TNFSF11)	OTJEPKEQ	TNF11_HUMAN	Decreases Expression	[21]
25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial (CYP27B1)	OTTK98BH	CP27B_HUMAN	Decreases Expression	[22]
Apoptosis-inducing factor 1, mitochondrial (AIFM1)	OTKPWB7Q	AIFM1_HUMAN	Affects Localization	[23]
Tropomyosin alpha-3 chain (TPM3)	OT5RU5G6	TPM3_HUMAN	Decreases Expression	[24]
Growth-regulated alpha protein (CXCL1)	OT3WCTZV	GROA_HUMAN	Affects Secretion	[25]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[26]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Decreases Activity	[27]
MHC class I polypeptide-related sequence A (MICA)	OTPEIEAR	MICA_HUMAN	Decreases Expression	[28]
Major histocompatibility complex class I-related gene protein (MR1)	OTZU3XX7	HMR1_HUMAN	Affects Expression	[29]
Arylamine N-acetyltransferase 2 (NAT2)	OTBPDQOY	ARY2_HUMAN	Increases Acetylation	[30]

References

• [1] ClinicalTrials.gov (NCT02434861) An Open Label, Single Dose, Three Part Study to Assess the Effects of Rolapitant (2 mg/mL IV Solution) on the Pharmacokinetics of Digoxin; Sulfasalazine; and the Cooperstown Cocktail (Midazolam, Omeprazole, Warfarin, Caffeine, and Dextromethorphan in Healthy Subjects
• [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: 5749).
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [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: 4840).
• [5] Sulfasalazine FDA Label
• [6] Netupitant and palonosetron trigger NK1 receptor internalization in NG108-15 cells. Exp Brain Res. 2014 Aug;232(8):2637-44.
• [7] Pharmacokinetic interactions of rolapitant with cytochrome P450 3A substrates in healthy subjects. J Clin Pharmacol. 2019 Apr;59(4):488-499.
• [8] Sulfasalazine down-regulates the expression of the angiogenic factors platelet-derived endothelial cell growth factor/thymidine phosphorylase and interleukin-8 in human monocytic-macrophage THP1 and U937 cells. Mol Pharmacol. 2004 Oct;66(4):1054-60.
• [9] [The effects of anti-inflammatory on activation of nuclear factor-kappaB and expression of cell adhesion molecules in patients with ulcerative colitis]. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2004 Oct;21(5):732-6.
• [10] The anti-inflammatory mechanism of sulfasalazine is related to adenosine release at inflamed sites. J Immunol. 1996 Mar 1;156(5):1937-41.
• [11] Emerging drugs for rheumatoid arthritis. Expert Opin Emerg Drugs. 2008 Mar;13(1):175-96.
• [12] Small intestinal efflux mediated by MRP2 and BCRP shifts sulfasalazine intestinal permeability from high to low, enabling its colonic targeting. Am J Physiol Gastrointest Liver Physiol. 2009 Aug;297(2):G371-7.
• [13] Curcumin inhibits the activity of ABCG2/BCRP1, a multidrug resistance-linked ABC drug transporter in mice. Pharm Res. 2009 Feb;26(2):480-7.
• [14] Peptide transporter substrate identification during permeability screening in drug discovery: comparison of transfected MDCK-hPepT1 cells to Caco-2 cells. Arch Pharm Res. 2007 Apr;30(4):507-18.
• [15] Small-Dosing Clinical Study: Pharmacokinetic, Pharmacogenomic (SLCO2B1 and ABCG2), and Interaction (Atorvastatin and Grapefruit Juice) Profiles of 5 Probes for OATP2B1 and BCRP. J Pharm Sci. 2017 Sep;106(9):2688-2694.
• [16] Urinary 6 beta-hydroxycortisol excretion in rheumatoid arthritis. Br J Rheumatol. 1997 Jan;36(1):54-8.
• [17] The influence of probiotic treatment on sulfasalazine metabolism in rat. Xenobiotica. 2012 Aug;42(8):791-7.
• [18] The role of intestinal bacteria in the metabolism of salicylazosulfapyridine. J Pharmacol Exp Ther. 1972 Jun;181(3):555-62.
• [19] Mapping human microbiome drug metabolism by gut bacteria and their genes. Nature. 2019 Jun;570(7762):462-467.
• [20] Chemotherapeutic drug-induced ABCG2 promoter demethylation as a novel mechanism of acquired multidrug resistance. Neoplasia. 2009 Dec;11(12):1359-70. doi: 10.1593/neo.91314.
• [21] Effects of disease-modifying antirheumatic drugs and antiinflammatory cytokines on human osteoclastogenesis through interaction with receptor activator of nuclear factor kappaB, osteoprotegerin, and receptor activator of nuclear factor kappaB ligand. Arthritis Rheum. 2004 Dec;50(12):3831-43. doi: 10.1002/art.20637.
• [22] Down-regulation by nuclear factor kappaB of human 25-hydroxyvitamin D3 1alpha-hydroxylase promoter. Mol Endocrinol. 2004 Oct;18(10):2440-50. doi: 10.1210/me.2002-0441. Epub 2004 Jul 8.
• [23] Molecular mechanisms of sulfasalazine-induced T-cell apoptosis. Br J Pharmacol. 2002 Nov;137(5):608-20. doi: 10.1038/sj.bjp.0704870.
• [24] Mesalamine suppresses the expression of TC22, a novel tropomyosin isoform associated with colonic neoplasia. Mol Pharmacol. 2009 Jul;76(1):183-91. doi: 10.1124/mol.109.056028. Epub 2009 Apr 15.
• [25] The effect of sulfasalazine on rheumatoid arthritic synovial tissue chemokine production. Exp Mol Pathol. 2002 Oct;73(2):84-92. doi: 10.1006/exmp.2002.2460.
• [26] [Activation of nuclear factor-kappaB and its relationship with cytokine gene expression in colonic mucosa of ulcerative colitis patients]. Zhonghua Nei Ke Za Zhi. 2002 Apr;41(4):252-5.
• [27] Sulfasalazine and BAY 11-7082 interfere with the nuclear factor-kappa B and I kappa B kinase pathway to regulate the release of proinflammatory cytokines from human adipose tissue and skeletal muscle in vitro. Endocrinology. 2005 Mar;146(3):1491-7. doi: 10.1210/en.2004-0809. Epub 2004 Nov 24.
• [28] NF-kappa B regulates expression of the MHC class I-related chain A gene in activated T lymphocytes. J Immunol. 2004 Nov 1;173(9):5583-90. doi: 10.4049/jimmunol.173.9.5583.
• [29] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [30] Adverse effects of sulfasalazine in patients with rheumatoid arthritis are associated with diplotype configuration at the N-acetyltransferase 2 gene. J Rheumatol. 2002 Dec;29(12):2492-9.