Details of the Drug Combination

General Information of Drug Combination (ID: DCJ8X55)

• Drug Combination Name: Pamidronate + Quinine
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Pamidronate (DMB4AVP): Small molecular drug
  Quinine (DMSWYF5): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 43.86
  Bliss Independence Score: 43.86
  Loewe Additivity Score: 53.94
  LHighest Single Agent (HSA) Score: 53.95

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Pamidronate

Disease Entry	ICD 11	Status	REF
Bone Paget disease	N.A.	Approved	[2]
Hypercalcaemia	5B91.0	Approved	[3]

Pamidronate Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Geranyltranstransferase (FDPS)	TTIKWV4	FPPS_HUMAN	Inhibitor	[5]

Pamidronate Interacts with 18 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[6]
Osteocalcin (BGLAP)	OTK1YLWQ	OSTCN_HUMAN	Increases Expression	[6]
Alkaline phosphatase, tissue-nonspecific isozyme (ALPL)	OTG7J4BP	PPBT_HUMAN	Increases Expression	[6]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Expression	[6]
Beta-2-microglobulin (B2M)	OTDWN6NX	B2MG_HUMAN	Decreases Expression	[6]
Tumor necrosis factor receptor superfamily member 11B (TNFRSF11B)	OTQ4W7MT	TR11B_HUMAN	Increases Expression	[7]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Expression	[8]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Decreases Expression	[9]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[10]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[10]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Expression	[11]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[11]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[11]
Transforming protein RhoA (RHOA)	OT6YOJ9N	RHOA_HUMAN	Decreases Expression	[11]
Ras-related protein Rap-1A (RAP1A)	OT5RH6TI	RAP1A_HUMAN	Decreases Prenylation	[12]
Rho-associated protein kinase 1 (ROCK1)	OTSXYVW1	ROCK1_HUMAN	Decreases Expression	[11]
Fibroblast growth factor 23 (FGF23)	OTZT523D	FGF23_HUMAN	Decreases Expression	[13]
Bcl-2-interacting killer (BIK)	OTTH1T3D	BIK_HUMAN	Increases Response To Substance	[14]

Indication(s) of Quinine

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[4]

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	[15]

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	[16]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[17]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[18]
Organic cation/carnitine transporter 2 (SLC22A5)	DT3HUVD	S22A5_HUMAN	Substrate	[19]
Organic cation/carnitine transporter 1 (SLC22A4)	DT2EG60	S22A4_HUMAN	Substrate	[20]
Na(+)/Cl(-) betaine/GABA transporter (SLC6A12)	DTBPTJF	S6A12_HUMAN	Substrate	[21]

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	[22]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[23]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[24]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[25]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[25]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[26]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[27]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[28]

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	[29]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[29]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[29]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases Expression	[30]
Solute carrier family 22 member 2 (SLC22A2)	OTGFK1AL	S22A2_HUMAN	Decreases Activity	[31]
Solute carrier family 22 member 1 (SLC22A1)	OT7817I4	S22A1_HUMAN	Decreases Activity	[31]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Affects Uptake	[32]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Decreases Activity	[33]
Glutathione S-transferase Mu 1 (GSTM1)	OTSBF2MO	GSTM1_HUMAN	Decreases Activity	[33]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Increases Expression	[30]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[34]
Sodium/hydrogen exchanger 7 (SLC9A7)	OTVDLTYA	SL9A7_HUMAN	Decreases Activity	[35]
Solute carrier organic anion transporter family member 1A2 (SLCO1A2)	OTO70C5O	SO1A2_HUMAN	Increases Uptake	[36]

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] Pamidronate FDA Label
• [3] 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: 7259).
• [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: 2510).
• [5] Detection of nonsterol isoprenoids by HPLC-MS/MS. Anal Biochem. 2008 Dec 1;383(1):18-24.
• [6] Pamidronate increases markers of bone formation in patients with multiple myeloma in plateau phase under interferon-alpha treatment. Calcif Tissue Int. 2001 May;68(5):285-90.
• [7] Bisphosphonates pamidronate and zoledronic acid stimulate osteoprotegerin production by primary human osteoblasts. Biochem Biophys Res Commun. 2002 Mar 1;291(3):680-6. doi: 10.1006/bbrc.2002.6510.
• [8] An in vitro and in vivo study of cytokines in the acute-phase response associated with bisphosphonates. Calcif Tissue Int. 1997 Nov;61(5):386-92. doi: 10.1007/s002239900353.
• [9] Expression profile and synthesis of different collagen types I, II, III, and V of human gingival fibroblasts, osteoblasts, and SaOS-2 cells after bisphosphonate treatment. Clin Oral Investig. 2010 Feb;14(1):51-8. doi: 10.1007/s00784-009-0312-2. Epub 2009 Jul 14.
• [10] Bisphosphonates induce apoptosis in human breast cancer cell lines. Br J Cancer. 2000 Apr;82(8):1459-68. doi: 10.1054/bjoc.1999.1131.
• [11] Pamidronate induced anti-proliferative, apoptotic, and anti-migratory effects in hepatocellular carcinoma. J Hepatol. 2006 Jan;44(1):142-50. doi: 10.1016/j.jhep.2005.09.022. Epub 2005 Nov 9.
• [12] Nitrogen-containing bisphosphonates induce apoptosis of Caco-2 cells in vitro by inhibiting the mevalonate pathway: a model of bisphosphonate-induced gastrointestinal toxicity. Bone. 2001 Oct;29(4):336-43. doi: 10.1016/s8756-3282(01)00589-0.
• [13] The role of fibroblast growth factor 23 for hypophosphatemia and abnormal regulation of vitamin D metabolism in patients with McCune-Albright syndrome. J Bone Miner Metab. 2005;23(3):231-7. doi: 10.1007/s00774-004-0589-9.
• [14] Caspase-independent induction of apoptosis in human melanoma cells by the proapoptotic Bcl-2-related protein Nbk / Bik. Oncogene. 2005 Nov 10;24(49):7369-80. doi: 10.1038/sj.onc.1208890.
• [15] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [16] 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.
• [17] Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol. 1997 Jul;16(7):871-81.
• [18] 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.
• [19] Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J Pharmacol Exp Ther. 1999 Nov;291(2):778-84.
• [20] Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. J Pharmacol Exp Ther. 1999 May;289(2):768-73.
• [21] The Transporter Classification Database (TCDB): recent advances. Nucleic Acids Res. 2016 Jan 4;44(D1):D372-9. (ID: 2.A.22.3.1)
• [22] Quinine induced simvastatin toxicity through cytochrome inhibition - a case report. BMC Geriatr. 2016 Oct 1;16(1):168.
• [23] 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.
• [24] 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.
• [25] Drug Interactions Flockhart Table
• [26] Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] 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.
• [32] 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.
• [33] 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.
• [34] 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.
• [35] 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.
• [36] 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.