Details of the Drug Combination

General Information of Drug Combination (ID: DCNYNIH)

• Drug Combination Name: MCI-186 + Atorvastatin
• Indication: Stroke; Status: Phase 1 [1]
• Component Drugs:
  MCI-186 (DM8ZHP1): Small molecular drug
  Atorvastatin (DMF28YC): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of MCI-186

Disease Entry	ICD 11	Status	REF
Amyotrophic lateral sclerosis	8B60.0	Approved	[2]

MCI-186 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Apoptosis regulator Bcl-2 (BCL-2)	TTJGNVC	BCL2_HUMAN	Regulator (upregulator)	[7]

MCI-186 Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic anion transporter 1 (SLC22A6)	DTQ23VB	S22A6_HUMAN	Substrate	[8]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[8]

MCI-186 Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[9]

MCI-186 Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Beta-nerve growth factor (NGF)	OTOLABJT	NGF_HUMAN	Increases Expression	[10]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Activity	[11]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[12]
Nitric oxide synthase 3 (NOS3)	OTLDT7NR	NOS3_HUMAN	Decreases Degradation	[13]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[12]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Phosphorylation	[10]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[12]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[12]

Indication(s) of Atorvastatin

Disease Entry	ICD 11	Status	REF
Acute coronary syndrome	BA41	Approved	[3]
Angina pectoris	BA40	Approved	[3]
Arteriosclerosis	BD40	Approved	[3]
Cardiovascular disease	BA00-BE2Z	Approved	[4]
Coronary atherosclerosis	N.A.	Approved	[3]
Hypercholesterolaemia	5C80.0	Approved	[3]
Hyperlipidemia	5C80.Z	Approved	[5]
Hyperlipidemia, familial combined, LPL related	N.A.	Approved	[3]
Hypertriglyceridemia	5C80.1	Approved	[3]
Inflammation	1A00-CA43.1	Approved	[3]
Non-insulin dependent diabetes	5A11	Approved	[3]
Psoriasis	EA90	Approved	[3]
Type-1/2 diabetes	5A10-5A11	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[6]
Stroke	8B20	Investigative	[3]
Venous thromboembolism	BD72	Investigative	[3]

Atorvastatin Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HMG-CoA reductase (HMGCR)	TTPADOQ	HMDH_HUMAN	Inhibitor	[17]
HUMAN MYD88NF-kappa-B proinflammatory pathway (MYD88-NFKB pathway)	TTDJB68	N.A.	Inhibitor	[18]

Atorvastatin Interacts with 7 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[19]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[20]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[21]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[22]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[23]
Monocarboxylate transporter 1 (SLC16A1)	DT342ZG	MOT1_HUMAN	Substrate	[24]
Monocarboxylate transporter 2 (SLC16A7)	DTLT3UG	MOT2_HUMAN	Substrate	[25]

Atorvastatin Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[26]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[27]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[28]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[29]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[30]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[31]

Atorvastatin Interacts with 93 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Stromelysin-1 (MMP3)	OTGBI74Z	MMP3_HUMAN	Increases ADR	[32]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[33]
Apolipoprotein E (APOE)	OTFOWL2H	APOE_HUMAN	Decreases Expression	[34]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Increases Expression	[35]
Kinesin-like protein KIF6 (KIF6)	OTDH3MR4	KIF6_HUMAN	Increases Response To Substance	[36]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Decreases Activity	[37]
Serum paraoxonase/arylesterase 1 (PON1)	OTD0Z2XO	PON1_HUMAN	Increases Expression	[38]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Increases Expression	[39]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Increases Activity	[39]
Phospholipid-transporting ATPase ABCA1 (ABCA1)	OT94G6BQ	ABCA1_HUMAN	Decreases Expression	[34]
Sterol 26-hydroxylase, mitochondrial (CYP27A1)	OT649C01	CP27A_HUMAN	Decreases Expression	[34]
Angiopoietin-2 (ANGPT2)	OTEQK65P	ANGP2_HUMAN	Increases Expression	[14]
Urokinase-type plasminogen activator (PLAU)	OTX0QGKK	UROK_HUMAN	Decreases Expression	[14]
Thrombospondin-1 (THBS1)	OT0ECWK3	TSP1_HUMAN	Decreases Expression	[14]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[14]
Nitric oxide synthase 3 (NOS3)	OTLDT7NR	NOS3_HUMAN	Increases Expression	[14]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Increases Activity	[40]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[41]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Expression	[42]
Solute carrier family 2, facilitated glucose transporter member 2 (SLC2A2)	OTBL2W7R	GTR2_HUMAN	Decreases Expression	[42]
Hexokinase-4 (GCK)	OTR3Q0NN	HXK4_HUMAN	Decreases Expression	[42]
Toll-like receptor 4 (TLR4)	OTP7ML3S	TLR4_HUMAN	Increases Expression	[43]
Toll-like receptor 2 (TLR2)	OTGO5P4R	TLR2_HUMAN	Increases Expression	[43]
Prothrombin (F2)	OTNFSM49	THRB_HUMAN	Decreases Activity	[44]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[45]
Low-density lipoprotein receptor (LDLR)	OTH559LU	LDLR_HUMAN	Increases Expression	[35]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Increases Expression	[46]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Decreases Expression	[15]
Interleukin-2 receptor subunit alpha (IL2RA)	OT0MWCHG	IL2RA_HUMAN	Affects Expression	[43]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Increases Expression	[47]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Decreases Expression	[48]
Transferrin receptor protein 1 (TFRC)	OT8ZPBDL	TFR1_HUMAN	Affects Expression	[43]
Osteocalcin (BGLAP)	OTK1YLWQ	OSTCN_HUMAN	Increases Expression	[47]
Apolipoprotein B-100 (APOB)	OTH0UOCZ	APOB_HUMAN	Decreases Expression	[49]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Affects Expression	[50]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[45]
Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)	OTM0GDTP	IF2A_HUMAN	Increases Phosphorylation	[51]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Decreases Expression	[52]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Decreases Expression	[53]
Intercellular adhesion molecule 1 (ICAM1)	OTTOIX77	ICAM1_HUMAN	Increases Expression	[15]
Integrin beta-1 (ITGB1)	OT6G1IAR	ITB1_HUMAN	Increases Expression	[54]
Rho-related GTP-binding protein RhoC (RHOC)	OTOLE1FT	RHOC_HUMAN	Decreases Localization	[55]
Monocyte differentiation antigen CD14 (CD14)	OT83GJ47	CD14_HUMAN	Decreases Expression	[56]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[57]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[52]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[57]
Integrin alpha-M (ITGAM)	OTAG6HWU	ITAM_HUMAN	Decreases Expression	[56]
Coagulation factor V (F5)	OTDMZ3LT	FA5_HUMAN	Decreases Activity	[44]
Bone morphogenetic protein 2 (BMP2)	OT23T37S	BMP2_HUMAN	Increases Expression	[47]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Expression	[52]
E-selectin (SELE)	OT33RZWY	LYAM2_HUMAN	Increases Expression	[15]
Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A)	OT2D9DOV	TNR1A_HUMAN	Decreases Expression	[53]
Integrin alpha-X (ITGAX)	OTOGIMHE	ITAX_HUMAN	Decreases Expression	[56]
Tumor necrosis factor receptor superfamily member 5 (CD40)	OT5YU2XB	TNR5_HUMAN	Decreases Expression	[43]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[57]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[57]
Interleukin-12 subunit alpha (IL12A)	OTDQT8GI	IL12A_HUMAN	Decreases Expression	[58]
CD40 ligand (CD40LG)	OT75Z6A6	CD40L_HUMAN	Decreases Expression	[59]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Increases Expression	[51]
Nicotinamide N-methyltransferase (NNMT)	OTFM38GU	NNMT_HUMAN	Increases Expression	[60]
T-lymphocyte activation antigen CD86 (CD86)	OTJCSBPC	CD86_HUMAN	Decreases Expression	[43]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA)	OTTOMI8J	PK3CA_HUMAN	Decreases Expression	[45]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[57]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Increases Expression	[57]
Tumor necrosis factor ligand superfamily member 6 (FASLG)	OTZARCHH	TNFL6_HUMAN	Increases Expression	[61]
Fatty acid synthase (FASN)	OTFII9KG	FAS_HUMAN	Increases Expression	[62]
Importin subunit alpha-1 (KPNA2)	OTU7FOE6	IMA1_HUMAN	Affects Localization	[63]
Microsomal triglyceride transfer protein large subunit (MTTP)	OTNUVSDT	MTP_HUMAN	Decreases Expression	[35]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[64]
Transforming protein RhoA (RHOA)	OT6YOJ9N	RHOA_HUMAN	Decreases Activity	[57]
Rho-related GTP-binding protein RhoB (RHOB)	OTHQFQF7	RHOB_HUMAN	Increases Expression	[55]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Affects Localization	[50]
E3 ubiquitin-protein ligase Mdm2 (MDM2)	OTOVXARF	MDM2_HUMAN	Increases Expression	[45]
CD83 antigen (CD83)	OT1V4WQF	CD83_HUMAN	Decreases Expression	[43]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[65]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[57]
Peroxisome proliferator-activated receptor alpha (PPARA)	OTK095PP	PPARA_HUMAN	Decreases Expression	[66]
Sterol regulatory element-binding protein 2 (SREBF2)	OTBXUNPL	SRBP2_HUMAN	Increases Localization	[62]
5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1)	OT7TNF0L	AAPK1_HUMAN	Increases Activity	[60]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[64]
Serum paraoxonase/arylesterase 2 (PON2)	OT55NCTD	PON2_HUMAN	Increases Expression	[67]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Decreases Expression	[46]
Nuclear factor erythroid 2-related factor 2 (NFE2L2)	OT0HENJ5	NF2L2_HUMAN	Decreases Expression	[50]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[65]
NAD-dependent protein deacetylase sirtuin-1 (SIRT1)	OTAYZMOY	SIR1_HUMAN	Increases Phosphorylation	[60]
Eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3)	OT0DZGY4	E2AK3_HUMAN	Increases Response To Substance	[51]
Tumor necrosis factor ligand superfamily member 10 (TNFSF10)	OT4PXBTA	TNF10_HUMAN	Increases Response To Substance	[68]
Liver carboxylesterase 1 (CES1)	OT9L0LR8	EST1_HUMAN	Increases ADR	[32]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Transport	[69]
Solute carrier organic anion transporter family member 2B1 (SLCO2B1)	OTERJ4VQ	SO2B1_HUMAN	Increases Uptake	[70]
Solute carrier organic anion transporter family member 1B1 (SLCO1B1)	OTNEN8QK	SO1B1_HUMAN	Decreases Transport	[71]
Solute carrier organic anion transporter family member 1B3 (SLCO1B3)	OTOM3BUH	SO1B3_HUMAN	Increases Uptake	[70]
Sister chromatid cohesion protein DCC1 (DSCC1)	OTPUVLZT	DCC1_HUMAN	Affects Response To Substance	[72]

References

• [1] ClinicalTrials.gov (NCT01518231) Autologous Hematopoietic Stem Cell Transplantation in Ischemic Stroke
• [2] 2017 FDA drug approvals.Nat Rev Drug Discov. 2018 Feb;17(2):81-85.
• [3] Atorvastatin FDA Label
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 205945.
• [6] ClinicalTrials.gov (NCT04380402) Atorvastatin in COVID-19. U.S. National Institutes of Health.
• [7] Emerging disease-modifying therapies for the treatment of motor neuron disease/amyotropic lateral sclerosis. Expert Opin Emerg Drugs. 2007 May;12(2):229-52.
• [8] Human organic anion transporters 1 (hOAT1/SLC22A6) and 3 (hOAT3/SLC22A8) transport edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one) and its sulfate conjugate. Drug Metab Dispos. 2007 Aug;35(8):1429-34.
• [9] A novel administration route for edaravone: I. Effects of metabolic inhibitors on skin permeability of edaravone. Int J Pharm. 2009 May 8;372(1-2):33-8.
• [10] Edaravone improves the expression of nerve growth factor in human astrocytes subjected to hypoxia/reoxygenation. Neurosci Res. 2010 Mar;66(3):284-9. doi: 10.1016/j.neures.2009.11.011. Epub 2009 Nov 30.
• [11] Edaravone inhibits rheumatoid synovial cell proliferation and migration. Free Radic Res. 2006 Feb;40(2):121-5. doi: 10.1080/10715760500401116.
• [12] A novel pyrazolone-based derivative induces apoptosis in human esophageal cells via reactive oxygen species (ROS) generation and caspase-dependent mitochondria-mediated pathway. Chem Biol Interact. 2015 Apr 25;231:1-9. doi: 10.1016/j.cbi.2015.02.004. Epub 2015 Feb 13.
• [13] Edaravone, a novel radical scavenger, inhibits oxidative modification of low-density lipoprotein (LDL) and reverses oxidized LDL-mediated reduction in the expression of endothelial nitric oxide synthase. Atherosclerosis. 2005 Mar;179(1):97-102. doi: 10.1016/j.atherosclerosis.2004.10.037. Epub 2004 Dec 19.
• [14] Atorvastatin affects several angiogenic mediators in human endothelial cells. Endothelium. 2005 Sep-Dec;12(5-6):233-41.
• [15] Markers of inflammation, thrombosis and endothelial activation correlate with carotid IMT regression in stable coronary disease after atorvastatin treatment. Nutr Metab Cardiovasc Dis. 2009 Sep;19(7):481-90. doi: 10.1016/j.numecd.2008.10.003. Epub 2009 Jan 26.
• [16] Simvastatin reduces VCAM-1 expression in human umbilical vein endothelial cells exposed to lipopolysaccharide. Inflamm Res. 2012 May;61(5):485-91. doi: 10.1007/s00011-012-0435-9. Epub 2012 Jan 15.
• [17] Equally potent inhibitors of cholesterol synthesis in human hepatocytes have distinguishable effects on different cytochrome P450 enzymes. Biopharm Drug Dispos. 2000 Dec;21(9):353-64.
• [18] Statin therapy in COVID-19 infection. Eur Heart J Cardiovasc Pharmacother. 2020 Apr 29. pii: pvaa042.
• [19] Tarascon Pocket Pharmacopoeia 2018 Classic Shirt-Pocket Edition.
• [20] Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism. Clin Chim Acta. 2009 Jul;405(1-2):49-52.
• [21] Influence of the flavonoids apigenin, kaempferol, and quercetin on the function of organic anion transporting polypeptides 1A2 and 2B1. Biochem Pharmacol. 2010 Dec 1;80(11):1746-53.
• [22] FDA Drug Development and Drug Interactions
• [23] Human platelets express organic anion-transporting peptide 2B1, an uptake transporter for atorvastatin. Drug Metab Dispos. 2009 May;37(5):1129-37.
• [24] H+-coupled nutrient, micronutrient and drug transporters in the mammalian small intestine. Exp Physiol. 2007 Jul;92(4):603-19.
• [25] Monocarboxylate Transporters in Drug Disposition: Role in the Toxicokinetics and Toxicodynamics of the Drug of Abuse GHB.
• [26] 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.
• [27] Atorvastatin glucuronidation is minimally and nonselectively inhibited by the fibrates gemfibrozil, fenofibrate, and fenofibric acid. Drug Metab Dispos. 2007 Aug;35(8):1315-24.
• [28] 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.
• [29] Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers.
• [30] Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
• [31] UGT1A1*28 is associated with decreased systemic exposure of atorvastatin lactone. Mol Diagn Ther. 2013 Aug;17(4):233-7.
• [32] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [33] Effect of atorvastatin and fluvastatin on the metabolism of midazolam by cytochrome P450 in vitro. Anaesthesia. 2005 Aug;60(8):747-53.
• [34] Effects of rosiglitazone and atorvastatin on the expression of genes that control cholesterol homeostasis in differentiating monocytes. Biochem Pharmacol. 2006 Feb 28;71(5):605-14.
• [35] Differential regulation of apolipoprotein B secretion from HepG2 cells by two HMG-CoA reductase inhibitors, atorvastatin and simvastatin. J Lipid Res. 1999 Jun;40(6):1078-89.
• [36] [Association of a polymorphic marker Trp719Arg of KIF6 gene with effects of atorvastatin and simvastatin in patients with early ischemic heart disease]. Kardiologiia. 2011;51(9):4-12.
• [37] Differential interaction of 3-hydroxy-3-methylglutaryl-coa reductase inhibitors with ABCB1, ABCC2, and OATP1B1. Drug Metab Dispos. 2005 Apr;33(4):537-46.
• [38] Effect of pitavastatin on transactivation of human serum paraoxonase 1 gene. Metabolism. 2005 Feb;54(2):142-50.
• [39] Identification of HMG-CoA reductase inhibitors as activators for human, mouse and rat constitutive androstane receptor. Drug Metab Dispos. 2005 Jul;33(7):924-9.
• [40] The effect of statins on lipids peroxidation and activities of antioxidants enzymes in patients with dyslipidemia. Przegl Lek. 2006;63(9):738-42.
• [41] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [42] Involvement of pregnane X receptor in the impaired glucose utilization induced by atorvastatin in hepatocytes. Biochem Pharmacol. 2016 Jan 15;100:98-111.
• [43] Differential effects of statins on relevant functions of human monocyte-derived dendritic cells. J Leukoc Biol. 2006 Mar;79(3):529-38. doi: 10.1189/jlb.0205064. Epub 2005 Dec 30.
• [44] Atorvastatin and quinapril inhibit blood coagulation in patients with coronary artery disease following 28 days of therapy. J Thromb Haemost. 2006 Nov;4(11):2397-404. doi: 10.1111/j.1538-7836.2006.02165.x. Epub 2006 Aug 14.
• [45] Atorvastatin induces MicroRNA-145 expression in HEPG2 cells via regulation of the PI3K/AKT signalling pathway. Chem Biol Interact. 2018 May 1;287:32-40. doi: 10.1016/j.cbi.2018.04.005. Epub 2018 Apr 6.
• [46] Additive beneficial effects of atorvastatin combined with amlodipine in patients with mild-to-moderate hypertension. Int J Cardiol. 2011 Feb 3;146(3):319-25. doi: 10.1016/j.ijcard.2009.07.002. Epub 2009 Aug 3.
• [47] Simvastatin and atorvastatin enhance gene expression of collagen type 1 and osteocalcin in primary human osteoblasts and MG-63 cultures. J Cell Biochem. 2007 Aug 15;101(6):1430-8. doi: 10.1002/jcb.21259.
• [48] Effects of atorvastatin on inflammation and oxidative stress. Heart Vessels. 2005 Jul;20(4):133-6. doi: 10.1007/s00380-005-0833-9.
• [49] Use of atorvastatin in hyperlipidemic hypertensive renal transplant recipients. Pediatr Nephrol. 2002 Jul;17(7):540-3. doi: 10.1007/s00467-002-0860-z. Epub 2002 May 25.
• [50] Atorvastatin induces mitochondrial dysfunction and cell apoptosis in HepG2 cells via inhibition of the Nrf2 pathway. J Appl Toxicol. 2019 Oct;39(10):1394-1404. doi: 10.1002/jat.3825. Epub 2019 Aug 18.
• [51] Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies. Cancer Res. 2010 Oct 1;70(19):7699-709. doi: 10.1158/0008-5472.CAN-10-1626. Epub 2010 Sep 28.
• [52] Simvastatin reduces expression of cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients. Arterioscler Thromb Vasc Biol. 2002 Jul 1;22(7):1194-9. doi: 10.1161/01.atv.0000022694.16328.cc.
• [53] The effects of atorvastatin (10 mg) on systemic inflammation in heart failure. Am J Cardiol. 2005 Dec 15;96(12):1699-704. doi: 10.1016/j.amjcard.2005.07.092. Epub 2005 Oct 28.
• [54] Statins regulate alpha2beta1-integrin expression and collagen I-dependent functions in human vascular smooth muscle cells. J Cardiovasc Pharmacol. 2003 Jan;41(1):89-96. doi: 10.1097/00005344-200301000-00012.
• [55] Combination of atorvastatin and celecoxib synergistically induces cell cycle arrest and apoptosis in colon cancer cells. Int J Cancer. 2008 May 1;122(9):2115-24. doi: 10.1002/ijc.23315.
• [56] Integrin expression on monocytes and lymphocytes in unstable angina short term effects of atorvastatin. Rom J Intern Med. 2007;45(2):193-9.
• [57] RhoA GTPase inactivation by statins induces osteosarcoma cell apoptosis by inhibiting p42/p44-MAPKs-Bcl-2 signaling independently of BMP-2 and cell differentiation. Cell Death Differ. 2006 Nov;13(11):1845-56. doi: 10.1038/sj.cdd.4401873. Epub 2006 Feb 10.
• [58] Treatment with atorvastatin alters the ratio of interleukin-12/interleukin-10 gene expression [corrected]. Eur J Clin Invest. 2003 Jan;33(1):88-91. doi: 10.1046/j.1365-2362.2003.01105.x.
• [59] Effect of atorvastatin on circulating proinflammatory T-lymphocyte subsets and soluble CD40 ligand in patients with stable coronary artery disease--a randomized, placebo-controlled study. Am Heart J. 2006 Jan;151(1):139. doi: 10.1016/j.ahj.2005.10.006.
• [60] Atorvastatin and pravastatin stimulate nitric oxide and reactive oxygen species generation, affect mitochondrial network architecture and elevate nicotinamide N-methyltransferase level in endothelial cells. J Appl Toxicol. 2021 Jul;41(7):1076-1088. doi: 10.1002/jat.4094. Epub 2020 Oct 19.
• [61] Decreased circulating Fas ligand in patients with familial combined hyperlipidemia or carotid atherosclerosis: normalization by atorvastatin. J Am Coll Cardiol. 2004 Apr 7;43(7):1188-94. doi: 10.1016/j.jacc.2003.10.046.
• [62] Effect of atorvastatin, simvastatin, and lovastatin on the metabolism of cholesterol and triacylglycerides in HepG2 cells. Biochem Pharmacol. 2001 Dec 1;62(11):1545-55. doi: 10.1016/s0006-2952(01)00790-0.
• [63] Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients. Viruses. 2021 Oct 15;13(10):2084. doi: 10.3390/v13102084.
• [64] Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells. Carcinogenesis. 2005 May;26(5):883-91. doi: 10.1093/carcin/bgi036. Epub 2005 Feb 10.
• [65] Atorvastatin mediates increases in intralesional BAX and BAK expression in human end-stage abdominal aortic aneurysms. Can J Physiol Pharmacol. 2009 Nov;87(11):915-22. doi: 10.1139/y09-085.
• [66] 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.
• [67] Decreased macrophage paraoxonase 2 expression in patients with hypercholesterolemia is the result of their increased cellular cholesterol content: effect of atorvastatin therapy. Arterioscler Thromb Vasc Biol. 2004 Jan;24(1):175-80. doi: 10.1161/01.ATV.0000104011.88939.06. Epub 2003 Oct 30.
• [68] Regulation of apoptosis in human melanoma and neuroblastoma cells by statins, sodium arsenite and TRAIL: a role of combined treatment versus monotherapy. Apoptosis. 2011 Dec;16(12):1268-84.
• [69] Atorvastatin transport in the Caco-2 cell model: contributions of P-glycoprotein and the proton-monocarboxylic acid co-transporter. Pharm Res. 2000 Feb;17(2):209-15. doi: 10.1023/a:1007525616017.
• [70] The influence of oral antidiabetic drugs on cellular drug uptake mediated by hepatic OATP family members. Basic Clin Pharmacol Toxicol. 2013 Apr;112(4):244-50. doi: 10.1111/bcpt.12031. Epub 2012 Dec 6.
• [71] Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15+C1007G, by using transient expression systems of HeLa and HEK293 cells. Pharmacogenet Genomics. 2005 Jul;15(7):513-22.
• [72] Identification of target and pathway of aspirin combined with Lipitor treatment in prostate cancer through integrated bioinformatics analysis. Toxicol Appl Pharmacol. 2022 Oct 1;452:116169. doi: 10.1016/j.taap.2022.116169. Epub 2022 Aug 1.