Details of the Drug Combination

General Information of Drug Combination (ID: DCATKSL)

• Drug Combination Name: Pitavastatin + Rosuvastatin
• Indication: Hypercholesterolemia; Status: Phase 1 [1]
• Component Drugs:
  Pitavastatin (DMJH792): N.A.
  Rosuvastatin (DMMIQ7G): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Pitavastatin

Disease Entry	ICD 11	Status	REF
Hypercholesterolaemia	5C80.0	Approved	[2]
Hyperlipidemia, familial combined, LPL related	N.A.	Approved	[2]

Pitavastatin Interacts with 6 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[5]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[6]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[7]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[8]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[9]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[10]

Pitavastatin Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Affects Transport	[5]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Affects Transport	[5]
Serum paraoxonase/arylesterase 1 (PON1)	OTD0Z2XO	PON1_HUMAN	Increases Expression	[11]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[12]
Phospholipid-transporting ATPase ABCA1 (ABCA1)	OT94G6BQ	ABCA1_HUMAN	Increases Expression	[13]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[14]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[14]
Ras-related protein Rap-1A (RAP1A)	OT5RH6TI	RAP1A_HUMAN	Decreases Expression	[14]
Peroxisome proliferator-activated receptor delta (PPARD)	OTI4WTOP	PPARD_HUMAN	Increases Expression	[13]
Peroxisome proliferator-activated receptor alpha (PPARA)	OTK095PP	PPARA_HUMAN	Increases Expression	[13]
Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)	OTXEE550	APR_HUMAN	Increases Expression	[14]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[14]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Affects Transport	[5]

Indication(s) of Rosuvastatin

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

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	[15]

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	[16]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[16]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[16]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[16]
Sodium/taurocholate cotransporting polypeptide (SLC10A1)	DT56EKP	NTCP_HUMAN	Substrate	[17]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[18]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[17]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[16]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[16]

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	[19]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[19]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[20]

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	[21]
Kinesin-like protein KIF6 (KIF6)	OTDH3MR4	KIF6_HUMAN	Increases ADR	[22]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Increases ADR	[23]

References

• [1] ClinicalTrials.gov (NCT01660191) A Study Comparing CoQ10 Levels While Taking 3 Different Statins. U.S. National Institutes of Health.
• [2] Pitavastatin FDA Label
• [3] Rosuvastatin FDA Label
• [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: 2954).
• [5] Involvement of BCRP (ABCG2) in the biliary excretion of pitavastatin. Mol Pharmacol. 2005 Sep;68(3):800-7.
• [6] ABCG2: a perspective. Adv Drug Deliv Rev. 2009 Jan 31;61(1):3-13.
• [7] Prediction of the in vivo OATP1B1-mediated drug-drug interaction potential of an investigational drug against a range of statins. Eur J Pharm Sci. 2012 Aug 30;47(1):244-55.
• [8] Transporter-mediated influx and efflux mechanisms of pitavastatin, a new inhibitor of HMG-CoA reductase. J Pharm Pharmacol. 2005 Oct;57(10):1305-11.
• [9] Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009 Oct;158(3):693-705.
• [10] Intestinal absorption of HMG-CoA reductase inhibitor pitavastatin mediated by organic anion transporting polypeptide and P-glycoprotein/multidrug resistance 1. Drug Metab Pharmacokinet. 2011;26(2):171-9.
• [11] Effect of pitavastatin on transactivation of human serum paraoxonase 1 gene. Metabolism. 2005 Feb;54(2):142-50.
• [12] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [13] Regulation mechanism of ABCA1 expression by statins in hepatocytes. Eur J Pharmacol. 2011 Jul 15;662(1-3):9-14. doi: 10.1016/j.ejphar.2011.04.043. Epub 2011 May 1.
• [14] Statin-induced Mitochondrial Priming Sensitizes Multiple Myeloma Cells to BCL2 and MCL-1 Inhibitors. Cancer Res Commun. 2023 Dec 8;3(12):2497-2509. doi: 10.1158/2767-9764.CRC-23-0350.
• [15] New dimension of statin action on ApoB atherogenicity. Clin Cardiol. 2003 Jan;26(1 Suppl 1):I7-10.
• [16] Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab Dispos. 2008 Oct;36(10):2014-23.
• [17] Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology. 2006 May;130(6):1793-806.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin. Clin Pharmacol Ther. 2010 May;87(5):558-62.
• [22] 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.
• [23] Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA. 2004 Jun 16;291(23):2821-7. doi: 10.1001/jama.291.23.2821.