Details of the Drug Combination

General Information of Drug Combination (ID: DCJ3HP0)

• Drug Combination Name: Pitavastatin + Darunavir
• Indication: Hyperlipidemia; Status: Phase 1 [1]
• Component Drugs:
  Pitavastatin (DMJH792): N.A.
  Darunavir (DMN3GCH): 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 Darunavir

Disease Entry	ICD 11	Status	REF
Human immunodeficiency virus infection	1C62	Approved	[3]
Human immunodeficiency virus-1 infection	1C62	Phase 3	[4]

Darunavir Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human immunodeficiency virus Protease (HIV PR)	TT5FNQT	POL_HV1B1	Modulator	[15]

Darunavir Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[16]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[17]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[18]

Darunavir Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[19]

References

• [1] ClinicalTrials.gov (NCT01695954) Pharmacokinetic Study of Pitavastatin and Ritonavir-Boosted Darunavir or Efavirenz
• [2] Pitavastatin FDA Label
• [3] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [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] 2006 drug approvals: finding the niche. Nat Rev Drug Discov. 2007 Feb;6(2):99-101.
• [16] Impact of drug transporters on cellular resistance towards saquinavir and darunavir. J Antimicrob Chemother. 2010 Nov;65(11):2319-28.
• [17] Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011 Mar;63(1):157-81.
• [18] P-glycoprotein mediates efflux transport of darunavir in human intestinal Caco-2 and ABCB1 gene-transfected renal LLC-PK1 cell lines. Biol Pharm Bull. 2009 Sep;32(9):1588-93.
• [19] Drug interactions with new and investigational antiretrovirals. Clin Pharmacokinet. 2009;48(4):211-41.