Details of the Drug Combination

General Information of Drug Combination (ID: DCUKWBF)

• Drug Combination Name: Clopidogrel + Cerivastatin
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Clopidogrel (DMOL54H): Small molecular drug
  Cerivastatin (DMXCM7H): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 6.49
  Bliss Independence Score: 6.49
  Loewe Additivity Score: 7
  LHighest Single Agent (HSA) Score: 7.09

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Clopidogrel

Disease Entry	ICD 11	Status	REF
Acute coronary syndrome	BA41	Approved	[2]
Atherosclerosis	BD40	Approved	[2]
Myocardial infarction	BA41-BA43	Approved	[2]
Thrombosis	DB61-GB90	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[4]
Intracranial embolism	8B22.1	Investigative	[2]

Clopidogrel Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
P2Y purinoceptor 12 (P2RY12)	TTZ1DT0	P2Y12_HUMAN	Antagonist	[7]

Clopidogrel Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]

Clopidogrel Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[10]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[11]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[11]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[12]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[13]

Clopidogrel Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[8]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases ADR	[14]
Stearoyl-CoA desaturase (SCD)	OTB1073G	SCD_HUMAN	Decreases Expression	[15]
C-C motif chemokine 4 (CCL4)	OT6B8P25	CCL4_HUMAN	Increases Expression	[16]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Increases Expression	[16]
Phosphoenolpyruvate carboxykinase, cytosolic (PCK1)	OTNWEJ5Y	PCKGC_HUMAN	Increases Expression	[15]
Glucose-6-phosphatase catalytic subunit 1 (G6PC1)	OTJ6FM9F	G6PC1_HUMAN	Decreases Expression	[15]
Tight junction protein ZO-1 (TJP1)	OTBDCUPK	ZO1_HUMAN	Decreases Expression	[17]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Affects Localization	[15]
Occludin (OCLN)	OTSUTVWL	OCLN_HUMAN	Decreases Expression	[17]
Thyroid hormone-inducible hepatic protein (THRSP)	OTKYE01L	THRSP_HUMAN	Increases Expression	[15]

Indication(s) of Cerivastatin

Disease Entry	ICD 11	Status	REF
Hyperlipidaemia	5C80	Approved	[5]
Multiple myeloma	2A83	Phase 1/2	[6]

Cerivastatin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HMG-CoA reductase (HMGCR)	TTPADOQ	HMDH_HUMAN	Inhibitor	[6]

Cerivastatin Interacts with 7 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[18]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[18]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[19]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[20]
Sodium/taurocholate cotransporting polypeptide (SLC10A1)	DT56EKP	NTCP_HUMAN	Substrate	[21]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[20]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[22]

Cerivastatin Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[23]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[24]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[24]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[25]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[23]

Cerivastatin Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Ryanodine receptor 2 (RYR2)	OT0PF19E	RYR2_HUMAN	Increases ADR	[26]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Clopidogrel 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: 7150).
• [4] Preventing Cardiac Complication of COVID-19 Disease With Early Acute Coronary Syndrome Therapy: A Randomised Controlled Trial. (C-19-ACS)
• [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: 2950).
• [6] Emerging therapies for multiple myeloma. Expert Opin Emerg Drugs. 2009 Mar;14(1):99-127.
• [7] P2Y12, a new platelet ADP receptor, target of clopidogrel. Semin Vasc Med. 2003 May;3(2):113-22.
• [8] Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther. 2006 Nov;80(5):486-501.
• [9] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [10] Clinical pharmacokinetics and pharmacodynamics of clopidogrel. Clin Pharmacokinet. 2015 Feb;54(2):147-66.
• [11] Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther. 2007 May;81(5):735-41.
• [12] Clopidogrel pathway. Pharmacogenet Genomics. 2010 Jul;20(7):463-5.
• [13] Impact of the CYP2C19 gene polymorphism on clopidogrel personalized drug regimen and the clinical outcomes. Clin Lab. 2016 Sep 1;62(9):1773-1780.
• [14] Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013 Sep;94(3):317-23. doi: 10.1038/clpt.2013.105. Epub 2013 May 22.
• [15] Identification of novel agonists by high-throughput screening and molecular modelling of human constitutive androstane receptor isoform 3. Arch Toxicol. 2019 Aug;93(8):2247-2264. doi: 10.1007/s00204-019-02495-6. Epub 2019 Jul 16.
• [16] Clopidogrel increases expression of chemokines in peripheral blood mononuclear cells in patients with coronary artery disease: results of a double-blind placebo-controlled study. J Thromb Haemost. 2006 Oct;4(10):2140-7. doi: 10.1111/j.1538-7836.2006.02131.x. Epub 2006 Jul 17.
• [17] Attenuated expression of the tight junction proteins is involved in clopidogrel-induced gastric injury through p38 MAPK activation. Toxicology. 2013 Feb 8;304:41-8. doi: 10.1016/j.tox.2012.11.020. Epub 2012 Dec 7.
• [18] Identification of the hepatic efflux transporters of organic anions using double-transfected Madin-Darby canine kidney II cells expressing human organic anion-transporting polypeptide 1B1 (OATP1B1)/multidrug resistance-associated protein 2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance protein. J Pharmacol Exp Ther. 2005 Sep;314(3):1059-67.
• [19] 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.
• [20] FDA Drug Development and Drug Interactions
• [21] Differential effect of genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP) and organic anion-transporting polypeptide 1B1 (OATP1B1) on the uptake of HMG-CoA reductase inhibitors. Xenobiotica. 2011 Jan;41(1):24-34.
• [22] pH-sensitive interaction of HMG-CoA reductase inhibitors (statins) with organic anion transporting polypeptide 2B1. Mol Pharm. 2011 Aug 1;8(4):1303-13.
• [23] Cerivastatin, genetic variants, and the risk of rhabdomyolysis. Pharmacogenet Genomics. 2011 May;21(5):280-8.
• [24] Drug Interactions Flockhart Table
• [25] Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
• [26] Cerivastatin, genetic variants, and the risk of rhabdomyolysis. Pharmacogenet Genomics. 2011 May;21(5):280-8.