Details of the Drug Combination

General Information of Drug Combination (ID: DCU21JE)

• Drug Combination Name: Arfolitixorin + Probenecid
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Arfolitixorin (DMIXMYK): Small molecular drug
  Probenecid (DMMFWOJ): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 7.46
  Bliss Independence Score: 7.46
  Loewe Additivity Score: 8.81
  LHighest Single Agent (HSA) Score: 8.87

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Arfolitixorin

Disease Entry	ICD 11	Status	REF
Colorectal cancer	2B91.Z	Phase 3	[2]

Indication(s) of Probenecid

Disease Entry	ICD 11	Status	REF
Acute gonococcal cervicitis	N.A.	Approved	[3]
Gout	FA25	Approved	[4]
Hyperuricaemia	5C55.Y	Approved	[4]

Probenecid Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Solute carrier family 22 member 8 (SLC22A8)	TTTQR47	S22A8_HUMAN	Blocker	[6]

Probenecid Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[7]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[8]
Monocarboxylate transporter 6 (SLC16A5)	DT3I124	MOT6_HUMAN	Substrate	[9]

Probenecid Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[10]

Probenecid Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Increases Activity	[11]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Decreases Activity	[12]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Expression	[13]
Taste receptor type 2 member 38 (TAS2R38)	OTX5MM36	T2R38_HUMAN	Decreases Activity	[14]
Taste receptor type 2 member 43 (TAS2R43)	OT70V8MZ	T2R43_HUMAN	Decreases Activity	[14]
Solute carrier family 22 member 6 (SLC22A6)	OTKRCBVM	S22A6_HUMAN	Decreases Activity	[15]
Organic anion transporter 7 (SLC22A9)	OTO4BJCC	S22A9_HUMAN	Decreases Activity	[15]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[16]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[16]
Sodium-coupled monocarboxylate transporter 1 (SLC5A8)	OTA0WELF	SC5A8_HUMAN	Decreases Activity	[17]
Organic anion transporter 3 (SLC22A8)	OT8BY933	S22A8_HUMAN	Decreases Expression	[18]
Solute carrier family 22 member 12 (SLC22A12)	OT72ZAWS	S22AC_HUMAN	Affects Activity	[19]
Solute carrier family 22 member 11 (SLC22A11)	OTAJLNJZ	S22AB_HUMAN	Decreases Activity	[20]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [2] ClinicalTrials.gov (NCT03750786) A Study to Compare the Efficacy of Arfolitixorin Versus Leucovorin in Combination With 5 Fluorouracil, Oxaliplatin, and Bevacizumab in Patients With Advanced Colorectal Cancer (AGENT). U.S. National Institutes of Health.
• [3] Probenecid 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: 4357).
• [5] Carboxylic acid drug-induced DNA nicking in HEK293 cells expressing human UDP-glucuronosyltransferases: role of acyl glucuronide metabolites and glycation pathways. Chem Res Toxicol. 2007 Oct;20(10):1520-7. doi: 10.1021/tx700188x. Epub 2007 Sep 20.
• [6] Transport of organic anions across the basolateral membrane of proximal tubule cells. Rev Physiol Biochem Pharmacol. 2003;146:95-158.
• [7] MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid. Int J Cancer. 2005 Sep 20;116(5):824-9.
• [8] Characterization of the efflux transport of 17beta-estradiol-D-17beta-glucuronide from the brain across the blood-brain barrier. J Pharmacol Exp Ther. 2001 Jul;298(1):316-22.
• [9] Quercetin, Morin, Luteolin, and Phloretin Are Dietary Flavonoid Inhibitors of Monocarboxylate Transporter 6. Mol Pharm. 2017 Sep 5;14(9):2930-2936.
• [10] Modulation of 3'-azido-3'-deoxythymidine catabolism by probenecid and acetaminophen in freshly isolated rat hepatocytes. Biochem Pharmacol. 1991 Sep 12;42(7):1475-80.
• [11] MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid. Int J Cancer. 2005 Sep 20;116(5):824-9. doi: 10.1002/ijc.21013.
• [12] Mercury induces multidrug resistance-associated protein gene through p38 mitogen-activated protein kinase. Toxicol Lett. 2005 Jan 15;155(1):143-50. doi: 10.1016/j.toxlet.2004.09.007.
• [13] Use of immortalized human hepatocytes to predict the magnitude of clinical drug-drug interactions caused by CYP3A4 induction. Drug Metab Dispos. 2006 Oct;34(10):1742-8.
• [14] Probenecid inhibits the human bitter taste receptor TAS2R16 and suppresses bitter perception of salicin. PLoS One. 2011;6(5):e20123.
• [15] Inhibition of organic anion transporter (OAT) activity by cigarette smoke condensate. Toxicol In Vitro. 2017 Oct;44:27-35.
• [16] Evaluation and mechanistic analysis of the cytotoxicity of the acyl glucuronide of nonsteroidal anti-inflammatory drugs. Drug Metab Dispos. 2014 Jan;42(1):1-8. doi: 10.1124/dmd.113.054478. Epub 2013 Oct 8.
• [17] The human tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter. J Physiol. 2004 Jun 15;557(Pt 3):719-31. doi: 10.1113/jphysiol.2004.063859. Epub 2004 Apr 16.
• [18] Targeting organic anion transporter 3 with probenecid as a novel anti-influenza a virus strategy. Antimicrob Agents Chemother. 2013 Jan;57(1):475-83. doi: 10.1128/AAC.01532-12. Epub 2012 Nov 5.
• [19] Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol. 2004 Jan;15(1):164-73. doi: 10.1097/01.asn.0000105320.04395.d0.
• [20] Neonicotinoid pesticides poorly interact with human drug transporters. J Biochem Mol Toxicol. 2019 Oct;33(10):e22379. doi: 10.1002/jbt.22379. Epub 2019 Jul 31.