Details of the Drug Combination

General Information of Drug Combination (ID: DCM4WII)

• Drug Combination Name: Tolbutamide + Tasisulam
• Indication: Lymphoma; Status: Phase 1 [1]
• Component Drugs:
  Tolbutamide (DM02AWV): Small molecular drug
  Tasisulam (DMJFRCT): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Tolbutamide

Disease Entry	ICD 11	Status	REF
Advanced cancer	2A00-2F9Z	Approved	[2]
Non-insulin dependent diabetes	5A11	Approved	[3]

Tolbutamide Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
ATP-binding cassette transporter C9 (ABCC9)	TTEF5MJ	ABCC9_HUMAN	Blocker	[5]
ATP-binding cassette transporter C8 (ABCC8)	TTP835K	ABCC8_HUMAN	Blocker	[5]

Tolbutamide Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Sulfonylurea receptor 1 (ABCC8)	DTI58LU	ABCC8_HUMAN	Substrate	[6]
Sulfonylurea receptor 2 (ABCC9)	DT3JCE6	ABCC9_HUMAN	Substrate	[6]

Tolbutamide Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Metabolism	[7]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[8]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[9]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[10]

Tolbutamide Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases Hydroxylation	[11]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Increases Hydroxylation	[12]
ATP-binding cassette sub-family C member 8 (ABCC8)	OTCWQ54I	ABCC8_HUMAN	Increases ADR	[13]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[14]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Increases Secretion	[15]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[16]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[17]
Tumor necrosis factor alpha-induced protein 3 (TNFAIP3)	OTVLI4DD	TNAP3_HUMAN	Decreases Expression	[18]
Tumor protein D52 (TPD52)	OTPKSK43	TPD52_HUMAN	Decreases Expression	[18]
ATP-sensitive inward rectifier potassium channel 11 (KCNJ11)	OTPUUELV	KCJ11_HUMAN	Decreases Activity	[19]
Programmed cell death protein 4 (PDCD4)	OTZ6NXUX	PDCD4_HUMAN	Decreases Expression	[18]

Indication(s) of Tasisulam

Disease Entry	ICD 11	Status	REF
Acute myeloid leukaemia	2A60	Phase 3	[4]

References

• [1] ClinicalTrials.gov (NCT01185548) A Drug Interaction Study of Tasisulam in Patients With Advanced Cancer or Lymphoma
• [2] Tolbutamide FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] ClinicalTrials.gov (NCT01006252) A Study of Tasisulam Versus Paclitaxel as Treatment for Metastatic Melanoma. U.S. National Institutes of Health.
• [5] Expression of an activating mutation in the gene encoding the KATP channel subunit Kir6.2 in mouse pancreatic beta cells recapitulates neonatal diabetes. J Clin Invest. 2009 Jan;119(1):80-90.
• [6] ABCC8 and ABCC9: ABC transporters that regulate K+ channels. Pflugers Arch. 2007 Feb;453(5):703-18.
• [7] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [8] Prediction of in vivo drug-drug interactions between tolbutamide and various sulfonamides in humans based on in vitro experiments. Drug Metab Dispos. 2000 Apr;28(4):475-81.
• [9] Effects of organic solvents on the activities of cytochrome P450 isoforms, UDP-dependent glucuronyl transferase, and phenol sulfotransferase in human hepatocytes. Drug Metab Dispos. 2001 Feb;29(2):141-4.
• [10] CYP2C19 participates in tolbutamide hydroxylation by human liver microsomes. Drug Metab Dispos. 2000 Mar;28(3):354-9.
• [11] Metabolic activity testing can underestimate acute drug cytotoxicity as revealed by HepG2 cell clones overexpressing cytochrome P450 2C19 and 3A4. Toxicology. 2019 Jan 15;412:37-47. doi: 10.1016/j.tox.2018.11.008. Epub 2018 Nov 27.
• [12] Identification of cytochrome P450 and arylamine N-acetyltransferase isoforms involved in sulfadiazine metabolism. Drug Metab Dispos. 2005 Jul;33(7):969-76.
• [13] 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.
• [14] 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.
• [15] Amino acid polymorphisms in the ATP-regulatable inward rectifier Kir6.2 and their relationships to glucose- and tolbutamide-induced insulin secretion, the insulin sensitivity index, and NIDDM. Diabetes. 1997 Mar;46(3):508-12. doi: 10.2337/diab.46.3.508.
• [16] A protein-coated magnetic beads as a tool for the rapid drug-protein binding study. J Pharm Biomed Anal. 2010 Jul 8;52(3):420-4. doi: 10.1016/j.jpba.2009.06.023. Epub 2009 Jun 18.
• [17] Interactions between Oroxylin A with the solute carrier transporters and ATP-binding cassette transporters: Drug transporters profile for this flavonoid. Chem Biol Interact. 2020 Jun 1;324:109097. doi: 10.1016/j.cbi.2020.109097. Epub 2020 Apr 16.
• [18] Human embryonic stem cell derived hepatocyte-like cells as a tool for in vitro hazard assessment of chemical carcinogenicity. Toxicol Sci. 2011 Dec;124(2):278-90. doi: 10.1093/toxsci/kfr225. Epub 2011 Aug 27.
• [19] Increased ATPase activity produced by mutations at arginine-1380 in nucleotide-binding domain 2 of ABCC8 causes neonatal diabetes. Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):18988-92. doi: 10.1073/pnas.0707428104. Epub 2007 Nov 19.