Details of the Drug Combination

General Information of Drug Combination (ID: DC62NA8)

• Drug Combination Name: Pazopanib + Carboplatin
• Indication: Cancer, Metastatic; Status: Phase 1 [1]
• Component Drugs:
  Pazopanib (DMF57DM): N.A.
  Carboplatin (DMG281S): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Pazopanib Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[5]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[5]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[6]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[5]

Pazopanib Interacts with 12 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[7]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Increases Expression	[7]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[8]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Expression	[7]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Secretion	[9]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[10]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Activity	[11]
Myeloblastin (PRTN3)	OT72MHP7	PRTN3_HUMAN	Increases Expression	[9]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[12]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[12]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[10]
HLA class I histocompatibility antigen protein P5 (HCP5)	OTV0YRI8	HCP5_HUMAN	Increases ADR	[13]

Indication(s) of Carboplatin

Disease Entry	ICD 11	Status	REF
Adenocarcinoma	2D40	Approved	[2]
Carcinoma	2A00-2F9Z	Approved	[2]
Cholangiocarcinoma	2C12.10	Approved	[2]
Cutaneous melanoma	2C30	Approved	[2]
Epithelial ovarian cancer	2B5D	Approved	[2]
Fallopian tube neoplasm	N.A.	Approved	[2]
Gastroesophageal junction adenocarcinoma	2B71	Approved	[2]
Lung adenocarcinoma	N.A.	Approved	[2]
Lung cancer	2C25.0	Approved	[2]
Non-small-cell lung cancer	2C25.Y	Approved	[2]
Ovarian cancer	2C73	Approved	[3]
Ovarian disorder	N.A.	Approved	[2]
Ovarian neoplasm	N.A.	Approved	[2]
Ovarian serous cystadenocarcinoma	N.A.	Approved	[2]
Small-cell lung cancer	2C25.Y	Approved	[2]
Lung large cell carcinoma	N.A.	Investigative	[2]
Neuroblastoma	2D11.2	Investigative	[2]

Carboplatin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human Deoxyribonucleic acid (hDNA)	TTUTN1I	NOUNIPROTAC	Modulator	[14]

Carboplatin Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
High affinity copper uptake protein 1 (SLC31A1)	DTP8L4F	COPT1_HUMAN	Substrate	[15]

Carboplatin Interacts with 7 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Glutathione S-transferase pi (GSTP1)	DEK6079	GSTP1_HUMAN	Metabolism	[16]
Glutathione S-transferase theta-1 (GSTT1)	DE3PKUG	GSTT1_HUMAN	Metabolism	[16]
Metallothionein-1A (MT1A)	DE5ME8A	MT1A_HUMAN	Metabolism	[16]
Metallothionein-2A (MT2A)	DEFKGT7	MT2_HUMAN	Metabolism	[16]
Myeloperoxidase (MPO)	DEA3U9Y	PERM_HUMAN	Metabolism	[16]
Quinone reductase 1 (NQO1)	DENP5RY	NQO1_HUMAN	Metabolism	[16]
Glutathione S-transferase mu-1 (GSTM1)	DEYZEJA	GSTM1_HUMAN	Metabolism	[16]

References

• [1] ClinicalTrials.gov (NCT01542047) A Combination of Pazopanib and Carboplatin in Advanced Solid Malignancies
• [2] Carboplatin 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: 7624).
• [4] Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism. Br J Cancer. 2010 Apr 27;102(9):1371-7. doi: 10.1038/sj.bjc.6605653. Epub 2010 Apr 13.
• [5] Pazopanib, a new therapy for metastatic soft tissue sarcoma. Expert Opin Pharmacother. 2013 May;14(7):929-35.
• [6] Pazopanib: the newest tyrosine kinase inhibitor for the treatment of advanced or metastatic renal cell carcinoma. Drugs. 2011 Mar 5;71(4):443-54.
• [7] Identification of approved drugs as potent inhibitors of pregnane X receptor activation with differential receptor interaction profiles. Arch Toxicol. 2018 Apr;92(4):1435-1451.
• [8] Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010 Dec; 118(2):485-500.
• [9] Activation of inflammasomes by tyrosine kinase inhibitors of vascular endothelial growth factor receptor: Implications for VEGFR TKIs-induced immune related adverse events. Toxicol In Vitro. 2021 Mar;71:105063. doi: 10.1016/j.tiv.2020.105063. Epub 2020 Dec 1.
• [10] 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.
• [11] Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals. Chem Res Toxicol. 2017 May 15;30(5):1219-1229. doi: 10.1021/acs.chemrestox.7b00048. Epub 2017 May 4.
• [12] MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model. Br J Cancer. 2016 Oct 11;115(8):920-928. doi: 10.1038/bjc.2016.263. Epub 2016 Aug 25.
• [13] HLA-B*57:01 Confers Susceptibility to Pazopanib-Associated Liver Injury in Patients with Cancer. Clin Cancer Res. 2016 Mar 15;22(6):1371-7. doi: 10.1158/1078-0432.CCR-15-2044. Epub 2015 Nov 6.
• [14] Inhibition of carboplatin-induced DNA interstrand cross-link repair by gemcitabine in patients receiving these drugs for platinum-resistant ovarian cancer.Clin Cancer Res.2010 Oct 1;16(19):4899-905.
• [15] Overcoming platinum drug resistance with copper-lowering agents. Anticancer Res. 2013 Oct;33(10):4157-61.
• [16] PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdiscip Rev Syst Biol Med. 2018 Jul;10(4):e1417. (ID: PA150642262)