Details of the Drug Combination

General Information of Drug Combination (ID: DCS2118)

• Drug Combination Name: Valsartan + Rosuvastatin
• Indication: Hypertension,; Status: Phase 3 [1]
• Component Drugs:
  Valsartan (DMREUQ6): Small molecular drug
  Rosuvastatin (DMMIQ7G): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Valsartan

Disease Entry	ICD 11	Status	REF
Chronic heart failure	BD1Z	Approved	[2]
Hypertension	BA00-BA04	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[4]
Nephropathy	GC2Z	Investigative	[2]

Valsartan Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Angiotensin II receptor type-1 (AGTR1)	TT8DBY3	AGTR1_HUMAN	Antagonist	[8]

Valsartan Interacts with 5 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[9]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[10]
Peptide transporter 1 (SLC15A1)	DT9G7XN	S15A1_HUMAN	Substrate	[11]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[12]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[9]

Valsartan Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[13]

Valsartan Interacts with 17 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Organic anion transporter 3 (SLC22A8)	OT8BY933	S22A8_HUMAN	Increases Expression	[14]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Increases Expression	[15]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[16]
Serum amyloid P-component (APCS)	OT76JZ8Z	SAMP_HUMAN	Decreases Expression	[17]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Decreases Export	[18]
Angiogenin (ANG)	OT3ECS6P	ANGI_HUMAN	Decreases Expression	[7]
Fatty acid-binding protein, adipocyte (FABP4)	OT3DKFOU	FABP4_HUMAN	Decreases Expression	[7]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Decreases Expression	[19]
Macrophage mannose receptor 1 (MRC1)	OTTVCOPT	MRC1_HUMAN	Decreases Expression	[7]
Cathepsin S (CTSS)	OT3PXIPM	CATS_HUMAN	Decreases Expression	[7]
Hematopoietic progenitor cell antigen CD34 (CD34)	OT1MOFLZ	CD34_HUMAN	Decreases Expression	[7]
Macrosialin (CD68)	OTOYEY3J	CD68_HUMAN	Decreases Expression	[7]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Expression	[7]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Decreases Expression	[7]
Coxsackievirus and adenovirus receptor (CXADR)	OT9ZP02A	CXAR_HUMAN	Decreases Expression	[20]
Scavenger receptor cysteine-rich type 1 protein M130 (CD163)	OT2E32LN	C163A_HUMAN	Decreases Expression	[7]
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Affects Response To Substance	[21]

Indication(s) of Rosuvastatin

Disease Entry	ICD 11	Status	REF
Arteriosclerosis	BD40	Approved	[5]
Hypercholesterolaemia	5C80.0	Approved	[6]
Hyperlipidemia, familial combined, LPL related	N.A.	Approved	[5]
Hypertriglyceridemia	5C80.1	Approved	[5]
Elevated C-reactive protein	MA14.15	Phase 3	[6]
Colon cancer	2B90.Z	Investigative	[5]
Precancerous condition	N.A.	Investigative	[5]
Stroke	8B20	Investigative	[5]

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	[22]

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	[23]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[23]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[23]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[23]
Sodium/taurocholate cotransporting polypeptide (SLC10A1)	DT56EKP	NTCP_HUMAN	Substrate	[24]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[25]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[24]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[23]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[23]

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	[26]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[26]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[27]

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	[28]
Kinesin-like protein KIF6 (KIF6)	OTDH3MR4	KIF6_HUMAN	Increases ADR	[29]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Increases ADR	[30]

References

• [1] ClinicalTrials.gov (NCT01918332) Efficacy and Safety of Valsartan 160mg and Rosuvastatin 20mg in Patients With Hypertension and Hyperlipidemia
• [2] Valsartan 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: 3937).
• [4] Valsartan for Prevention of Acute Respiratory Distress Syndrome in Hospitalized Patients With SARS-COV-2 (COVID-19) Infection Disease
• [5] Rosuvastatin FDA Label
• [6] 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).
• [7] Valsartan improves adipose tissue function in humans with impaired glucose metabolism: a randomized placebo-controlled double-blind trial. PLoS One. 2012;7(6):e39930. doi: 10.1371/journal.pone.0039930. Epub 2012 Jun 29.
• [8] Radioligand binding assays: application of [(125)I]angiotensin II receptor binding. Methods Mol Biol. 2009;552:131-41.
• [9] Involvement of transporters in the hepatic uptake and biliary excretion of valsartan, a selective antagonist of the angiotensin II AT1-receptor, in humans. Drug Metab Dispos. 2006 Jul;34(7):1247-54.
• [10] Regulation of Organic Anion Transporting Polypeptides (OATP) 1B1- and OATP1B3-Mediated Transport: An Updated Review in the Context of OATP-Mediated Drug-Drug Interactions. Int J Mol Sci. 2018 Mar 14;19(3). pii: E855.
• [11] High-affinity interaction of sartans with H+/peptide transporters. Drug Metab Dispos. 2009 Jan;37(1):143-9.
• [12] Prediction of the overall renal tubular secretion and hepatic clearance of anionic drugs and a renal drug-drug interaction involving organic anion transporter 3 in humans by in vitro uptake experiments. Drug Metab Dispos. 2011 Jun;39(6):1031-8.
• [13] In vitro inhibition screening of human hepatic P450 enzymes by five angiotensin-II receptor antagonists. Eur J Clin Pharmacol. 2000 May;56(2):135-40.
• [14] Uric acid accumulation in the kidney triggers mast cell degranulation and aggravates renal oxidative stress. Toxicology. 2023 Jan 1;483:153387. doi: 10.1016/j.tox.2022.153387. Epub 2022 Dec 1.
• [15] Angiotensin II receptor blockade in normotensive subjects: A direct comparison of three AT1 receptor antagonists. Hypertension. 1999 Mar;33(3):850-5. doi: 10.1161/01.hyp.33.3.850.
• [16] [The relationship between the gene polymorphism of TGF-beta1 and early renal injury in patients with essential hypertension, and the effect of the gene polymorphism of TGF- beta1 on the individual treatment with valsartan]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2007 Aug;24(4):428-31.
• [17] C-reactive protein in heart failure: prognostic value and the effect of valsartan. Circulation. 2005 Sep 6;112(10):1428-34. doi: 10.1161/CIRCULATIONAHA.104.508465. Epub 2005 Aug 29.
• [18] Is renoprotection by angiotensin receptor blocker dependent on blood pressure?: the Saitama Medical School, Albuminuria Reduction in Diabetics with Valsartan (STAR) study. Hypertens Res. 2007 Jun;30(6):529-33. doi: 10.1291/hypres.30.529.
• [19] Effects of valsartan on circulating brain natriuretic peptide and norepinephrine in symptomatic chronic heart failure: the Valsartan Heart Failure Trial (Val-HeFT). Circulation. 2002 Nov 5;106(19):2454-8. doi: 10.1161/01.cir.0000036747.68104.ac.
• [20] Antiviral effect of Bosentan and Valsartan during coxsackievirus B3 infection of human endothelial cells. J Gen Virol. 2010 Aug;91(Pt 8):1959-1970. doi: 10.1099/vir.0.020065-0. Epub 2010 Apr 14.
• [21] Comparing antihypertensive effect and plasma ciclosporin concentration between amlodipine and valsartan regimens in hypertensive renal transplant patients receiving ciclosporin therapy. Am J Cardiovasc Drugs. 2011 Dec 1;11(6):401-9. doi: 10.2165/11593800-000000000-00000.
• [22] New dimension of statin action on ApoB atherogenicity. Clin Cardiol. 2003 Jan;26(1 Suppl 1):I7-10.
• [23] Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab Dispos. 2008 Oct;36(10):2014-23.
• [24] Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology. 2006 May;130(6):1793-806.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin. Clin Pharmacol Ther. 2010 May;87(5):558-62.
• [29] 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.
• [30] Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA. 2004 Jun 16;291(23):2821-7. doi: 10.1001/jama.291.23.2821.