Details of the Drug Combination

General Information of Drug Combination (ID: DCEYDIO)

• Drug Combination Name: Sulfamethoxazole + Trimethoprim
• Indication: Bronchitis; Status: Phase 1 [1]
• Component Drugs:
  Sulfamethoxazole (DMB08GE): Small molecular drug
  Trimethoprim (DMM7CHK): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Sulfamethoxazole

Disease Entry	ICD 11	Status	REF
Acute otitis media	AB00	Approved	[2]
Bacillary dysentery	1A02	Approved	[2]
Bacterial infection	1A00-1C4Z	Approved	[3]
Inclusion conjunctivitis	N.A.	Approved	[2]
Pneumocystis pneumonia	CA40.20	Approved	[2]
Tuberculosis	1B10-1B14	Approved	[2]
Infection of P. falciparum	1F40	Investigative	[4]

Sulfamethoxazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial Dihydropteroate synthetase (Bact folP)	TT4ILYC	DHPS_ECOLI	Inhibitor	[7]

Sulfamethoxazole Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
RNA cytidine acetyltransferase (hALP)	DEZV4AP	NAT10_HUMAN	Metabolism	[9]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[10]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[11]
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_HUMAN	Metabolism	[12]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[12]

Sulfamethoxazole Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Arylamine N-acetyltransferase 2 (NAT2)	OTBPDQOY	ARY2_HUMAN	Increases Metabolism	[13]
Myeloperoxidase (MPO)	OTOOXLIN	PERM_HUMAN	Increases ADR	[14]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Increases ADR	[14]
Phytanoyl-CoA dioxygenase, peroxisomal (PHYH)	OTUG4BWA	PAHX_HUMAN	Decreases Expression	[15]
Pirin (PIR)	OT8ALXHU	PIR_HUMAN	Increases Expression	[16]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Secretion	[16]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[17]
HLA class I histocompatibility antigen, alpha chain G (HLA-G)	OTMLK1KN	HLAG_HUMAN	Affects Expression	[18]

Indication(s) of Trimethoprim

Disease Entry	ICD 11	Status	REF
Acute otitis media	AB00	Approved	[5]
Bacillary dysentery	1A02	Approved	[5]
Blepharoconjunctivitis	N.A.	Approved	[5]
Pneumocystis pneumonia	CA40.20	Approved	[5]
Tuberculosis	1B10-1B14	Approved	[5]
Urinary tract infection	GC08	Approved	[6]

Trimethoprim Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dihydrofolate reductase (DHFR)	TTYZVDJ	DYR_HUMAN	Modulator	[19]

Trimethoprim Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[20]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[21]

Trimethoprim Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[22]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[23]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[24]

Trimethoprim Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Decreases Activity	[25]
HLA class II histocompatibility antigen gamma chain (CD74)	OTO16X4Q	HG2A_HUMAN	Affects Expression	[18]
HLA class II histocompatibility antigen, DO beta chain (HLA-DOB)	OTKADDUB	DOB_HUMAN	Affects Expression	[18]
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Increases Transport	[26]

References

• [1] ClinicalTrials.gov (NCT02879981) A Safety Study of Balsamic Bactrim in Pediatric Participants With Acute Bronchitis
• [2] Sulfamethoxazole FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40.
• [5] Trimethoprim FDA Label
• [6] Has nature already identified all useful antibacterial targets Curr Opin Microbiol. 2008 Oct;11(5):387-92.
• [7] In vitro activities of novel antifolate drug combinations against Plasmodium falciparum and human granulocyte CFUs. Antimicrob Agents Chemother. 1995 Apr;39(4):948-52.
• [8] The effect of cimetidine on the formation of sulfamethoxazole hydroxylamine in patients with human immunodeficiency virus. J Clin Pharmacol. 1998 May;38(5):463-6.
• [9] Crystallization and preliminary X-ray characterization of arylamine N-acetyltransferase C (BanatC) from Bacillus anthracis. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2007 Oct 1;63(Pt 10):862-4.
• [10] Sulfamethoxazole and its metabolite nitroso sulfamethoxazole stimulate dendritic cell costimulatory signaling. J Immunol. 2007 May 1;178(9):5533-42.
• [11] Reduction of sulfamethoxazole and dapsone hydroxylamines by a microsomal enzyme system purified from pig liver and pig and human liver microsomes. Life Sci. 2005 May 27;77(2):205-19.
• [12] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [13] Analysis of nucleotide diversity of NAT2 coding region reveals homogeneity across Native American populations and high intra-population diversity. Pharmacogenomics J. 2007 Apr;7(2):144-52. doi: 10.1038/sj.tpj.6500407. Epub 2006 Jul 18.
• [14] 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.
• [15] A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005 Feb;83(2):282-92.
• [16] Evaluation of the sensitizing potential of antibiotics in vitro using the human cell lines THP-1 and MUTZ-LC and primary monocyte-derived dendritic cells. Toxicol Appl Pharmacol. 2012 Aug 1;262(3):283-92.
• [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] 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.
• [19] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [20] Improving the prediction of the brain disposition for orally administered drugs using BDDCS. Adv Drug Deliv Rev. 2012 Jan;64(1):95-109.
• [21] Identification of novel substrates and structure-activity relationship of cellular uptake mediated by human organic cation transporters 1 and 2. J Med Chem. 2013 Sep 26;56(18):7232-42.
• [22] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [23] Pioglitazone is metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with CYP2C8 inhibitors. Basic Clin Pharmacol Toxicol. 2006 Jul;99(1):44-51.
• [24] Trimethoprim and sulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9, respectively. Drug Metab Dispos. 2002 Jun;30(6):631-5.
• [25] Cytochrome P450 inhibition potential of new psychoactive substances of the tryptamine class. Toxicol Lett. 2016 Jan 22;241:82-94.
• [26] Caki-1 cells as a model system for the interaction of renally secreted drugs with OCT3. Nephron Physiol. 2008;108(2):p18-28. doi: 10.1159/000115040. Epub 2008 Feb 4.