Details of the Drug Combination

General Information of Drug Combination (ID: DCSV7DS)

• Drug Combination Name: Regorafenib + Rosuvastatin
• Indication: Neoplasms; Status: Phase 1 [1]
• Component Drugs:
  Regorafenib (DMHSY1I): Small molecular drug
  Rosuvastatin (DMMIQ7G): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Regorafenib

Disease Entry	ICD 11	Status	REF
Gastrointestinal stromal tumour	2B5B	Approved	[2]
Metastasis from malignant tumor of colon	N.A.	Approved	[2]
Metastatic colorectal cancer	2B91	Approved	[3]

Regorafenib Interacts with 3 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Tyrosine-protein kinase Kit (KIT)	TTX41N9	KIT_HUMAN	Modulator	[7]
Proto-oncogene c-Ret (RET)	TT4DXQT	RET_HUMAN	Modulator	[7]
Vascular endothelial growth factor receptor 2 (KDR)	TTUTJGQ	VGFR2_HUMAN	Modulator	[7]

Regorafenib Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[8]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[10]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[8]

Regorafenib Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_HUMAN	Metabolism	[11]

Regorafenib Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[6]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Decreases Expression	[6]
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Secretion	[12]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[6]
Tumor necrosis factor receptor superfamily member 6 (FAS)	OTP9XG86	TNR6_HUMAN	Increases Activity	[6]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[6]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[6]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[6]
Tumor necrosis factor ligand superfamily member 6 (FASLG)	OTZARCHH	TNFL6_HUMAN	Increases Activity	[6]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Decreases Expression	[6]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[6]

Indication(s) of Rosuvastatin

Disease Entry	ICD 11	Status	REF
Arteriosclerosis	BD40	Approved	[4]
Hypercholesterolaemia	5C80.0	Approved	[5]
Hyperlipidemia, familial combined, LPL related	N.A.	Approved	[4]
Hypertriglyceridemia	5C80.1	Approved	[4]
Elevated C-reactive protein	MA14.15	Phase 3	[5]
Colon cancer	2B90.Z	Investigative	[4]
Precancerous condition	N.A.	Investigative	[4]
Stroke	8B20	Investigative	[4]

Rosuvastatin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HMG-CoA reductase (HMGCR)	TTPADOQ	HMDH_HUMAN	Inhibitor	[13]

Rosuvastatin Interacts with 9 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[14]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[14]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[14]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[14]
Sodium/taurocholate cotransporting polypeptide (SLC10A1)	DT56EKP	NTCP_HUMAN	Substrate	[15]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[16]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[15]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[14]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[14]

Rosuvastatin Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[17]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[17]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[18]

Rosuvastatin Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Increases ADR	[19]
Kinesin-like protein KIF6 (KIF6)	OTDH3MR4	KIF6_HUMAN	Increases ADR	[20]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Increases ADR	[21]

References

• [1] ClinicalTrials.gov (NCT02106845) Effect of Regorafenib on Digoxin and Rosuvastatin in Patients With Advanced Solid Malignant Tumors.
• [2] Regorafenib 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: 5891).
• [4] Rosuvastatin FDA Label
• [5] 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: 2954).
• [6] Regorefenib induces extrinsic/intrinsic apoptosis and inhibits MAPK/NF-B-modulated tumor progression in bladder cancer in vitro and in vivo. Environ Toxicol. 2019 Jun;34(6):679-688. doi: 10.1002/tox.22734. Epub 2019 Feb 25.
• [7] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [8] Regorafenib is transported by the organic anion transporter 1B1 and the multidrug resistance protein 2. Biol Pharm Bull. 2015;38(4):582-6.
• [9] Brain and Testis Accumulation of Regorafenib is Restricted by Breast Cancer Resistance Protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1). Pharm Res. 2015 Jul;32(7):2205-16.
• [10] KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017 Jan 4;45(D1):D353-D361. (dg:DG01913)
• [11] FDA Label of Regorafenib. The 2020 official website of the U.S. Food and Drug Administration.
• [12] Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes. Toxicol Lett. 2018 Jul;291:138-148. doi: 10.1016/j.toxlet.2018.04.010. Epub 2018 Apr 12.
• [13] New dimension of statin action on ApoB atherogenicity. Clin Cardiol. 2003 Jan;26(1 Suppl 1):I7-10.
• [14] Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab Dispos. 2008 Oct;36(10):2014-23.
• [15] Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology. 2006 May;130(6):1793-806.
• [16] The contribution of organic anion transporters OAT1 and OAT3 to the renal uptake of rosuvastatin. J Pharmacol Exp Ther. 2007 Sep;322(3):1221-7.
• [17] Effects of acid and lactone forms of eight HMG-CoA reductase inhibitors on CYP-mediated metabolism and MDR1-mediated transport. Pharm Res. 2006 Mar;23(3):506-12.
• [18] Pharmacokinetics of rosuvastatin when coadministered with rifampicin in healthy males: a randomized, single-blind, placebo-controlled, crossover study. Clin Ther. 2008 Jul;30(7):1283-9.
• [19] ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin. Clin Pharmacol Ther. 2010 May;87(5):558-62.
• [20] Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials: the CARE and WOSCOPS trials. J Am Coll Cardiol. 2008 Jan 29;51(4):435-43. doi: 10.1016/j.jacc.2007.05.057.
• [21] Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA. 2004 Jun 16;291(23):2821-7. doi: 10.1001/jama.291.23.2821.