Details of the Drug Combination

General Information of Drug Combination (ID: DC6CU7A)

• Drug Combination Name: Quinine + Pentamidine
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Quinine (DMSWYF5): Small molecular drug
  Pentamidine (DMHZJCG): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 37.66
  Bliss Independence Score: 37.66
  Loewe Additivity Score: 54.15
  LHighest Single Agent (HSA) Score: 54.15

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Quinine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[2]

Quinine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
E3 ubiquitin-protein ligase COP1 (RFWD2)	TT05DLS	COP1_HUMAN	Modulator	[6]

Quinine Interacts with 6 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[8]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[9]
Organic cation/carnitine transporter 2 (SLC22A5)	DT3HUVD	S22A5_HUMAN	Substrate	[10]
Organic cation/carnitine transporter 1 (SLC22A4)	DT2EG60	S22A4_HUMAN	Substrate	[11]
Na(+)/Cl(-) betaine/GABA transporter (SLC6A12)	DTBPTJF	S6A12_HUMAN	Substrate	[12]

Quinine Interacts with 8 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[13]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[14]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[15]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[16]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[16]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[17]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[18]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[19]

Quinine Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[20]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[20]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[20]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Expression	[21]
Solute carrier family 22 member 2 (SLC22A2)	OTGFK1AL	S22A2_HUMAN	Decreases Activity	[22]
Solute carrier family 22 member 1 (SLC22A1)	OT7817I4	S22A1_HUMAN	Decreases Activity	[22]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Affects Uptake	[23]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Decreases Activity	[24]
Glutathione S-transferase Mu 1 (GSTM1)	OTSBF2MO	GSTM1_HUMAN	Decreases Activity	[24]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Expression	[21]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[25]
Sodium/hydrogen exchanger 7 (SLC9A7)	OTVDLTYA	SL9A7_HUMAN	Decreases Activity	[26]
Solute carrier organic anion transporter family member 1A2 (SLCO1A2)	OTO70C5O	SO1A2_HUMAN	Increases Uptake	[27]

Indication(s) of Pentamidine

Disease Entry	ICD 11	Status	REF
African trypanosomiasis	1F51	Approved	[3]
Fungal infection	1F29-1F2F	Approved	[4]
Pneumocystis pneumonia	CA40.20	Approved	[3]
Human immunodeficiency virus infection	1C62	Withdrawn from market	[5]

Pentamidine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tryptase alpha/beta-1 (Tryptase)	TTM1TDX	TRYB1_HUMAN	Inhibitor	[29]

Pentamidine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[30]

Pentamidine Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[31]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[31]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[31]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[31]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[31]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[32]

Pentamidine Interacts with 26 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[20]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[20]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[20]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[20]
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Increases Expression	[28]
Alpha-1-antichymotrypsin (SERPINA3)	OT9BP2S0	AACT_HUMAN	Increases Expression	[28]
Serine protease hepsin (HPN)	OT7QNA61	HEPS_HUMAN	Increases Expression	[28]
Fatty acid-binding protein, liver (FABP1)	OTR34ETM	FABPL_HUMAN	Decreases Expression	[28]
Asparagine synthetase (ASNS)	OT8R922G	ASNS_HUMAN	Increases Expression	[28]
Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3)	OT2HZK5M	GTR3_HUMAN	Decreases Expression	[28]
Lanosterol synthase (LSS)	OT9W2SFH	LSS_HUMAN	Decreases Expression	[28]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[28]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Increases Expression	[28]
Fibronectin type III domain-containing protein 4 (FNDC4)	OTOQK0WK	FNDC4_HUMAN	Increases Expression	[28]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[28]
Nibrin (NBN)	OT73B5MD	NBN_HUMAN	Affects Localization	[33]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[34]
HLA class II histocompatibility antigen, DQ beta 1 chain (HLA-DQB1)	OTVVI3UI	DQB1_HUMAN	Affects Expression	[35]
Interferon gamma receptor 1 (IFNGR1)	OTCTQBWW	INGR1_HUMAN	Increases Expression	[36]
Histone H2AX (H2AX)	OT18UX57	H2AX_HUMAN	Affects Localization	[33]
Double-strand break repair protein MRE11 (MRE11)	OTGU8TZM	MRE11_HUMAN	Decreases Activity	[33]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[37]
Serine-protein kinase ATM (ATM)	OTQVOHLT	ATM_HUMAN	Decreases Activity	[33]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[38]
Histone acetyltransferase KAT5 (KAT5)	OTL7257A	KAT5_HUMAN	Decreases Activity	[33]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Increases Activity	[39]

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] 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: 2510).
• [3] Pentamidine FDA Label
• [4] Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40.
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [7] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [8] Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol. 1997 Jul;16(7):871-81.
• [9] Comparison of type I and type II organic cation transport by organic cation transporters and organic anion-transporting polypeptides. J Pharmacol Exp Ther. 2001 Jul;298(1):110-5.
• [10] Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J Pharmacol Exp Ther. 1999 Nov;291(2):778-84.
• [11] Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. J Pharmacol Exp Ther. 1999 May;289(2):768-73.
• [12] The Transporter Classification Database (TCDB): recent advances. Nucleic Acids Res. 2016 Jan 4;44(D1):D372-9. (ID: 2.A.22.3.1)
• [13] Quinine induced simvastatin toxicity through cytochrome inhibition - a case report. BMC Geriatr. 2016 Oct 1;16(1):168.
• [14] The roles of cytochrome P450 3A4 and 1A2 in the 3-hydroxylation of quinine in vivo. Clin Pharmacol Ther. 1999 Nov;66(5):454-60.
• [15] Inhibition of cytochrome P450 2D6: structure-activity studies using a series of quinidine and quinine analogues. Chem Res Toxicol. 2003 Apr;16(4):450-9.
• [16] Drug Interactions Flockhart Table
• [17] Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
• [18] Identification of human cytochrome P450 isoforms involved in the 3-hydroxylation of quinine by human live microsomes and nine recombinant human cytochromes P450. J Pharmacol Exp Ther. 1996 Dec;279(3):1327-34.
• [19] Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001 Feb;120(2):525-33.
• [20] Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s. Drug Metab Dispos. 2001 Jan;29(1):30-5.
• [21] Cytochrome P450 1A1/2 induction by antiparasitic drugs: dose-dependent increase in ethoxyresorufin O-deethylase activity and mRNA caused by quinine, primaquine and albendazole in HepG2 cells. Eur J Clin Pharmacol. 2002 Nov;58(8):537-42.
• [22] Involvement of aryl hydrocarbon receptor in the cytotoxicity of corannulene and its derivatives. Toxicol Lett. 2020 Mar 15;321:114-121. doi: 10.1016/j.toxlet.2019.12.012. Epub 2019 Dec 9.
• [23] Stereoselective transport of hydrophilic quaternary drugs by human MDR1 and rat Mdr1b P-glycoproteins. Br J Pharmacol. 2002 Apr;135(7):1685-94. doi: 10.1038/sj.bjp.0704620.
• [24] Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Int J Cancer. 2002 Feb 10;97(5):700-5.
• [25] Voltage-dependent profile of human ether-a-go-go-related gene channel block is influenced by a single residue in the S6 transmembrane domain. Mol Pharmacol. 2003 May;63(5):1051-8. doi: 10.1124/mol.63.5.1051.
• [26] Molecular cloning and characterization of a novel (Na+,K+)/H+ exchanger localized to the trans-Golgi network. J Biol Chem. 2001 May 18;276(20):17387-94. doi: 10.1074/jbc.M101319200. Epub 2001 Feb 26.
• [27] Expression of Organic Anion Transporting Polypeptide 1A2 in Red Blood Cells and Its Potential Impact on Antimalarial Therapy. Drug Metab Dispos. 2016 Oct;44(10):1562-8. doi: 10.1124/dmd.116.069807. Epub 2016 Aug 8.
• [28] 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.
• [29] Inhibitors of tryptase for the treatment of mast cell-mediated diseases. Curr Pharm Des. 1998 Oct;4(5):381-96.
• [30] Transport of dicationic drugs pentamidine and furamidine by human organic cation transporters. Drug Metab Dispos. 2009 Feb;37(2):424-30.
• [31] Identification of human cytochrome P(450)s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data. Eur J Clin Pharmacol. 2003 Sep;59(5-6):429-42.
• [32] Value of preemptive CYP2C19 genotyping in allogeneic stem cell transplant patients considered for pentamidine administration. Clin Transplant. 2011 May-Jun;25(3):E271-5.
• [33] Bisbenzamidine derivative, pentamidine represses DNA damage response through inhibition of histone H2A acetylation. Mol Cancer. 2010 Feb 9;9:34. doi: 10.1186/1476-4598-9-34.
• [34] Profiling the immunotoxicity of chemicals based on in vitro evaluation by a combination of the Multi-ImmunoTox assay and the IL-8 Luc assay. Arch Toxicol. 2018 Jun;92(6):2043-2054. doi: 10.1007/s00204-018-2199-7. Epub 2018 Mar 29.
• [35] 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.
• [36] Antileishmanial drugs cause up-regulation of interferon-gamma receptor 1, not only in the monocytes of visceral leishmaniasis cases but also in cultured THP1 cells. Ann Trop Med Parasitol. 2003 Apr;97(3):245-57. doi: 10.1179/000349803235001714.
• [37] Identification of human Ether--go-go related gene modulators by three screening platforms in an academic drug-discovery setting. Assay Drug Dev Technol. 2010 Dec;8(6):727-42. doi: 10.1089/adt.2010.0331.
• [38] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [39] Investigation of imatinib and other approved drugs as starting points for antidiabetic drug discovery with FXR modulating activity. Biochem Pharmacol. 2012 Jun 15;83(12):1674-81. doi: 10.1016/j.bcp.2012.02.027. Epub 2012 Mar 7.