Details of the Drug Combination

General Information of Drug Combination (ID: DCLZAYY)

Drug Combination Name
Alogliptin Pioglitazone
Indication
Disease Entry Status REF
Type-2 diabetes Approved [1]
Component Drugs Alogliptin   DM8WI3R Pioglitazone   DMKJ485
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Alogliptin
Disease Entry ICD 11 Status REF
Type-2 diabetes 5A11 Approved [2]
Alogliptin Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Dipeptidyl peptidase 4 (DPP-4) TTDIGC1 DPP4_HUMAN Inhibitor [7]
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Alogliptin Interacts with 2 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [8]
Cytochrome P450 2D6 (CYP2D6) DECB0K3 CP2D6_HUMAN Metabolism [8]
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Indication(s) of Pioglitazone
Disease Entry ICD 11 Status REF
Amyotrophic lateral sclerosis 8B60.0 Approved [3]
Diabetic complication 5A2Y Approved [4]
Non-insulin dependent diabetes 5A11 Approved [3]
Type-2 diabetes 5A11 Phase 3 [5]
Endometriosis GA10 Investigative [3]
Obesity 5B81 Investigative [6]
Pioglitazone Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Peroxisome proliferator-activated receptor gamma (PPAR-gamma) TTZMAO3 PPARG_HUMAN Agonist [12]
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Pioglitazone Interacts with 4 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [13]
Cytochrome P450 2C8 (CYP2C8) DES5XRU CP2C8_HUMAN Metabolism [14]
Cytochrome P450 2C9 (CYP2C9) DE5IED8 CP2C9_HUMAN Metabolism [15]
Prostaglandin G/H synthase 1 (COX-1) DE073H6 PGH1_HUMAN Metabolism [16]
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Pioglitazone Interacts with 97 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Cytochrome b-245 light chain (CYBA) OT16N9ZO CY24A_HUMAN Decreases Expression [17]
Hydroxymethylglutaryl-CoA synthase, cytoplasmic (HMGCS1) OTCO26FV HMCS1_HUMAN Increases Expression [18]
Phospholipid-transporting ATPase ABCA1 (ABCA1) OT94G6BQ ABCA1_HUMAN Increases Expression [19]
Acetyl-CoA acetyltransferase, mitochondrial (ACAT1) OTJC60Q7 THIL_HUMAN Decreases Expression [19]
Perilipin-2 (PLIN2) OTRXJ9UN PLIN2_HUMAN Increases Expression [19]
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2) OT02MSKN 3BHS2_HUMAN Decreases Expression [20]
Bile salt export pump (ABCB11) OTRU7THO ABCBB_HUMAN Decreases Activity [21]
Choriogonadotropin subunit beta variant 1 (CGB1) OT7NFGXF CGB1_HUMAN Increases Expression [9]
Immunoglobulin mu Fc receptor (FCMR) OTI7I47T FCMR_HUMAN Increases Expression [9]
Protein FAM13A (FAM13A) OTZ6GN0Q FA13A_HUMAN Increases Expression [9]
Keratin, type II cytoskeletal 6A (KRT6A) OT392M5T K2C6A_HUMAN Decreases Expression [9]
Protein S100-A8 (S100A8) OTVMOB3F S10A8_HUMAN Decreases Expression [9]
Pleckstrin (PLEK) OTB73XXA PLEK_HUMAN Decreases Expression [9]
Matrilysin (MMP7) OTVT3SEJ MMP7_HUMAN Decreases Expression [9]
Choriogonadotropin subunit beta 3 (CGB3) OTVM2SU3 CGB3_HUMAN Increases Expression [9]
Interleukin-8 (CXCL8) OTS7T5VH IL8_HUMAN Decreases Expression [9]
C-C motif chemokine 3 (CCL3) OTW2H3ND CCL3_HUMAN Decreases Expression [9]
C-C motif chemokine 3-like 1 (CCL3L1) OTQXCYB1 CL3L1_HUMAN Decreases Expression [9]
Natriuretic peptides B (NPPB) OTSN2IPY ANFB_HUMAN Decreases Expression [9]
fMet-Leu-Phe receptor (FPR1) OTFF9I6W FPR1_HUMAN Decreases Expression [9]
Glutathione peroxidase 3 (GPX3) OT6PK94R GPX3_HUMAN Increases Expression [9]
Solute carrier family 2, facilitated glucose transporter member 5 (SLC2A5) OTZNYEKF GTR5_HUMAN Decreases Expression [9]
Fibulin-1 (FBLN1) OT5MHHOP FBLN1_HUMAN Increases Expression [9]
G-protein coupled receptor 183 (GPR183) OTRILX7G GP183_HUMAN Decreases Expression [9]
AP-1 complex subunit sigma-2 (AP1S2) OTZHJFYI AP1S2_HUMAN Decreases Expression [9]
Insulin gene enhancer protein ISL-1 (ISL1) OTVNVKAX ISL1_HUMAN Increases Expression [9]
Regulator of G-protein signaling 1 (RGS1) OTGXJYMG RGS1_HUMAN Decreases Expression [9]
Chitotriosidase-1 (CHIT1) OTPQR0A6 CHIT1_HUMAN Decreases Expression [9]
Baculoviral IAP repeat-containing protein 3 (BIRC3) OT3E95KB BIRC3_HUMAN Decreases Expression [9]
Four and a half LIM domains protein 1 (FHL1) OTN535SU FHL1_HUMAN Increases Expression [9]
Chorionic somatomammotropin hormone-like 1 (CSHL1) OTQKU2F5 CSHL_HUMAN Increases Expression [9]
kinase isozyme 4, mitochondrial (PDK4) OTCMHMBZ PDK4_HUMAN Increases Expression [9]
Ankyrin repeat domain-containing protein SOWAHC (SOWAHC) OTI86ECP SWAHC_HUMAN Increases Expression [9]
Mitochondrial amidoxime-reducing component 1 (MTARC1) OTNBE033 MARC1_HUMAN Increases Expression [9]
Isthmin-2 (ISM2) OT4K7KON ISM2_HUMAN Increases Expression [9]
Mitochondrial adenyl nucleotide antiporter SLC25A24 (SLC25A24) OT3ZNGEL SCMC1_HUMAN Decreases Expression [9]
SPOC domain-containing protein 1 (SPOCD1) OTF4K46N SPOC1_HUMAN Increases Expression [9]
Transmembrane protein 91 (TMEM91) OT6AQNY8 TMM91_HUMAN Increases Expression [9]
Retrotransposon-derived protein PEG10 (PEG10) OTWD2278 PEG10_HUMAN Increases Expression [9]
Mast cell-expressed membrane protein 1 (MCEMP1) OTCZC9ZM MCEM1_HUMAN Increases Expression [9]
Retinol dehydrogenase 10 (RDH10) OTL9FSGF RDH10_HUMAN Increases Expression [9]
Leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2) OT1O2K47 LIRA2_HUMAN Decreases Expression [9]
C-type lectin domain family 1 member A (CLEC1A) OTG7Q02A CLC1A_HUMAN Increases Expression [9]
Prostamide/prostaglandin F synthase (PRXL2B) OTY5G543 PXL2B_HUMAN Decreases Expression [9]
Uncharacterized protein C1orf54 (C1ORF54) OTXFDXKJ CA054_HUMAN Decreases Expression [9]
MICOS complex subunit MIC25 (CHCHD6) OT8F9BHW MIC25_HUMAN Decreases Expression [9]
Acetyl-CoA acetyltransferase, cytosolic (ACAT2) OTZ092ZJ THIC_HUMAN Decreases Expression [9]
Very long chain fatty acid elongase 4 (ELOVL4) OT2M9W26 ELOV4_HUMAN Increases Expression [9]
Membrane-spanning 4-domains subfamily A member 7 (MS4A7) OT4X45JZ MS4A7_HUMAN Increases Expression [9]
Regulator of cell cycle RGCC (RGCC) OTYJMLWM RGCC_HUMAN Decreases Expression [9]
Transducin-like enhancer protein 6 (TLE6) OTB84O0U TLE6_HUMAN Increases Expression [9]
Endogenous retroviral envelope protein HEMO (ERVMER34-1) OTECWJ0Y MER34_HUMAN Increases Expression [9]
GTPase IMAP family member 4 (GIMAP4) OTEUZH06 GIMA4_HUMAN Decreases Expression [9]
SLAM family member 5 (CD84) OTAY5B0F SLAF5_HUMAN Decreases Expression [9]
Procollagen C-endopeptidase enhancer 2 (PCOLCE2) OTSUEQZ1 PCOC2_HUMAN Increases Expression [9]
C-type lectin domain family 4 member A (CLEC4A) OTNLPK2C CLC4A_HUMAN Decreases Expression [9]
Nuclear receptor subfamily 1 group I member 2 (NR1I2) OTC5U0N5 NR1I2_HUMAN Affects Localization [10]
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Increases Expression [10]
Alternative prion protein (PRNP) OTE85L1Q APRIO_HUMAN Increases Expression [22]
Unconventional myosin-Ic (MYO1C) OT69L39Y MYO1C_HUMAN Increases Expression [11]
Proepiregulin (EREG) OTRM4NQY EREG_HUMAN Increases Expression [23]
Nephrin (NPHS1) OT21JD3P NPHN_HUMAN Increases Expression [24]
C-reactive protein (CRP) OT0RFT8F CRP_HUMAN Decreases Expression [25]
Amyloid-beta precursor protein (APP) OTKFD7R4 A4_HUMAN Decreases Expression [26]
Plasminogen activator inhibitor 1 (SERPINE1) OTT0MPQ3 PAI1_HUMAN Increases Expression [27]
ATP synthase subunit beta, mitochondrial (ATP5F1B) OTLFZUQK ATPB_HUMAN Decreases Expression [28]
Protein S100-A9 (S100A9) OTOARHCS S10A9_HUMAN Increases Expression [29]
Hepatocyte growth factor receptor (MET) OT7K55MU MET_HUMAN Increases Expression [23]
C-C motif chemokine 5 (CCL5) OTSCA5CK CCL5_HUMAN Decreases Response To Substance [30]
Fatty acid-binding protein, adipocyte (FABP4) OT3DKFOU FABP4_HUMAN Increases Expression [31]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Decreases Phosphorylation [32]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Decreases Phosphorylation [32]
G1/S-specific cyclin-D3 (CCND3) OTNKPQ22 CCND3_HUMAN Decreases Expression [33]
Cyclin-dependent kinase inhibitor 1 (CDKN1A) OTQWHCZE CDN1A_HUMAN Decreases Expression [33]
Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) OTTOMI8J PK3CA_HUMAN Decreases Expression [11]
Cyclin-dependent kinase inhibitor 1B (CDKN1B) OTNY5LLZ CDN1B_HUMAN Increases Expression [32]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN) OTOWDUNT PTEN_HUMAN Increases Expression [11]
Cell division control protein 42 homolog (CDC42) OT5QBC5M CDC42_HUMAN Decreases Expression [11]
Small ribosomal subunit protein eS6 (RPS6) OTT4D1LN RS6_HUMAN Decreases Expression [11]
Peptidyl-prolyl cis-trans isomerase FKBP1A (FKBP1A) OT6285L4 FKB1A_HUMAN Increases Expression [11]
Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA) OT83PT85 PP2AA_HUMAN Increases Expression [11]
Nucleobindin-2 (NUCB2) OTHO6JWN NUCB2_HUMAN Increases Stability [34]
Tumor necrosis factor-inducible gene 6 protein (TNFAIP6) OT1SLUZH TSG6_HUMAN Increases Expression [23]
Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform (PPP2R2B) OTSFVC82 2ABB_HUMAN Increases Expression [11]
Transcription factor A, mitochondrial (TFAM) OTXXV5V7 TFAM_HUMAN Decreases Expression [28]
Eukaryotic translation initiation factor 4E-binding protein 2 (EIF4EBP2) OT3M8WEU 4EBP2_HUMAN Increases Expression [11]
Peptidyl-prolyl cis-trans isomerase FKBP8 (FKBP8) OT8RPSOC FKBP8_HUMAN Increases Expression [11]
GTP-binding protein Rheb (RHEB) OTFLTSEC RHEB_HUMAN Increases Expression [11]
Serine/threonine-protein kinase STK11 (STK11) OT1YZSP3 STK11_HUMAN Increases Expression [11]
PTB-containing, cubilin and LRP1-interacting protein (PID1) OT5YJ7FI PCLI1_HUMAN Increases Expression [23]
Regulatory-associated protein of mTOR (RPTOR) OT4TQZ9F RPTOR_HUMAN Increases Phosphorylation [32]
Intelectin-1 (ITLN1) OT7ZLJVV ITLN1_HUMAN Increases Expression [35]
Type II iodothyronine deiodinase (DIO2) OTGPNSLH IOD2_HUMAN Increases Activity [36]
DNA damage-inducible transcript 4-like protein (DDIT4L) OT26Z2KN DDT4L_HUMAN Increases Expression [11]
Tribbles homolog 3 (TRIB3) OTG5OS7X TRIB3_HUMAN Decreases Expression [37]
DNA damage-inducible transcript 4 protein (DDIT4) OTHY8SY4 DDIT4_HUMAN Increases Expression [11]
Telomere length regulation protein TEL2 homolog (TELO2) OT2YQ9L8 TELO2_HUMAN Increases Expression [11]
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⏷ Show the Full List of 97 DOT(s)

References

1 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
2 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: 6319).
3 Pioglitazone 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: 2694).
5 ClinicalTrials.gov (NCT01183013) 30 Week Parallel Group Comparison Study of Linagliptin + Pioglitazone (5+15, 5+30 and 5+45 mg) qd Versus Respective Monotherapies, Followed by a Comparison of 5mg+30mg and 5mg+45mg Versus Respective Monotherapies in Type 2 Diabetes for up to 54 Weeks. U.S. National Institutes of Health.
6 Obesity: pathophysiology and clinical management. Curr Med Chem. 2009;16(4):506-21.
7 Clinical pipeline report, company report or official report of Takeda (2009).
8 An update on the clinical pharmacology of the dipeptidyl peptidase 4 inhibitor alogliptin used for the treatment of type 2 diabetes mellitus. Clin Exp Pharmacol Physiol. 2015 Dec;42(12):1225-38.
9 Peroxisome proliferator activated receptor gamma (PPAR-gama) ligand pioglitazone regulated gene networks in term human primary trophoblast cells. Reprod Toxicol. 2018 Oct;81:99-107.
10 A comprehensive evaluation of anti-diabetic drugs on nuclear receptor PXR platform. Toxicol In Vitro. 2019 Oct;60:347-358.
11 Effects of metformin and pioglitazone combination on apoptosis and AMPK/mTOR signaling pathway in human anaplastic thyroid cancer cells. J Biochem Mol Toxicol. 2020 Oct;34(10):e22547. doi: 10.1002/jbt.22547. Epub 2020 Jun 26.
12 Functional PPAR-gamma receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas. Nat Med. 2002 Nov;8(11):1281-7.
13 Pioglitazone is metabolised by CYP2C8 and CYP3A4 in vitro: potential for interactions with CYP2C8 inhibitors. Basic Clin Pharmacol Toxicol. 2006 Jul;99(1):44-51.
14 The role of human CYP2C8 and CYP2C9 variants in pioglitazone metabolism in vitro. Basic Clin Pharmacol Toxicol. 2009 Dec;105(6):374-9.
15 Current clinical evidence on pioglitazone pharmacogenomics. Front Pharmacol. 2013 Nov 26;4:147.
16 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.
17 The ligands/activators for peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma increase Cu2+,Zn2+-superoxide dismutase and decrease p22phox message expressions in primary endothelial cells. Metabolism. 2001 Jan;50(1):3-11.
18 PPAR gamma ligands, troglitazone and pioglitazone, up-regulate expression of HMG-CoA synthase and HMG-CoA reductase gene in THP-1 macrophages. FEBS Lett. 2002 Jun 5;520(1-3):177-81.
19 Comparison of the effects of pioglitazone and rosiglitazone on macrophage foam cell formation. Biochem Biophys Res Commun. 2004 Oct 22;323(3):782-8.
20 Pioglitazone inhibits androgen production in NCI-H295R cells by regulating gene expression of CYP17 and HSD3B2. Mol Pharmacol. 2007 Mar;71(3):787-98.
21 Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010 Dec; 118(2):485-500.
22 Co-Administration of Melatonin Effectively Enhances the Therapeutic Effects of Pioglitazone on Mesenchymal Stem Cells Undergoing Indoxyl Sulfate-Induced Senescence through Modulation of Cellular Prion Protein Expression. Int J Mol Sci. 2018 May 4;19(5):1367. doi: 10.3390/ijms19051367.
23 An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
24 Transcriptional regulation of nephrin gene by peroxisome proliferator-activated receptor-gamma agonist: molecular mechanism of the antiproteinuric effect of pioglitazone. J Am Soc Nephrol. 2006 Jun;17(6):1624-32. doi: 10.1681/ASN.2005090983. Epub 2006 May 10.
25 Endocannabinoid receptor blockade reduces alanine aminotransferase in polycystic ovary syndrome independent of weight loss. BMC Endocr Disord. 2017 Jul 14;17(1):41. doi: 10.1186/s12902-017-0194-2.
26 Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain. 2005 Jun;128(Pt 6):1442-53. doi: 10.1093/brain/awh452. Epub 2005 Apr 7.
27 PPAR activation induces acute PAI-1 gene expression in the liver but not in adipose tissues of diabetic model mice. Thromb Res. 2011 Nov;128(5):e81-5. doi: 10.1016/j.thromres.2011.06.020. Epub 2011 Jul 14.
28 Troglitazone induces cytotoxicity in part by promoting the degradation of peroxisome proliferator-activated receptor co-activator-1 protein. Br J Pharmacol. 2010 Oct;161(4):771-81. doi: 10.1111/j.1476-5381.2010.00900.x.
29 Prediction of drug-induced liver injury using keratinocytes. J Appl Toxicol. 2017 Jul;37(7):863-872. doi: 10.1002/jat.3435. Epub 2017 Jan 31.
30 Telmisartan inhibits CD4-positive lymphocyte migration independent of the angiotensin type 1 receptor via peroxisome proliferator-activated receptor-gamma. Hypertension. 2008 Feb;51(2):259-66. doi: 10.1161/HYPERTENSIONAHA.107.099028. Epub 2007 Dec 24.
31 Human adipocyte fatty acid-binding protein (aP2) gene promoter-driven reporter assay discriminates nonlipogenic peroxisome proliferator-activated receptor gamma ligands. J Pharmacol Exp Ther. 2004 Nov;311(2):467-75. doi: 10.1124/jpet.104.068254. Epub 2004 Jul 23.
32 Pioglitazone, a PPAR agonist, attenuates PDGF-induced vascular smooth muscle cell proliferation through AMPK-dependent and AMPK-independent inhibition of mTOR/p70S6K and ERK signaling. Biochem Pharmacol. 2016 Feb 1;101:54-70. doi: 10.1016/j.bcp.2015.11.026. Epub 2015 Nov 28.
33 Thiazolidinediones inhibit proliferation of microvascular and macrovascular cells by a PPARgamma-independent mechanism. Diabetologia. 2005 Mar;48(3):586-94. doi: 10.1007/s00125-005-1672-z. Epub 2005 Feb 24.
34 Troglitazone, a ligand of peroxisome proliferator-activated receptor-{gamma}, stabilizes NUCB2 (Nesfatin) mRNA by activating the ERK1/2 pathway: isolation and characterization of the human NUCB2 gene. Endocrinology. 2010 Jun;151(6):2494-503. doi: 10.1210/en.2009-1169. Epub 2010 Apr 28.
35 Cardioprotective properties of omentin-1 in type 2 diabetes: evidence from clinical and in vitro studies. PLoS One. 2013;8(3):e59697. doi: 10.1371/journal.pone.0059697. Epub 2013 Mar 29.
36 Type 2 deiodinase expression is induced by peroxisomal proliferator-activated receptor-gamma agonists in skeletal myocytes. Endocrinology. 2009 Apr;150(4):1976-83. doi: 10.1210/en.2008-0938. Epub 2008 Nov 26.
37 PML-RAR interaction with TRIB3 impedes PPAR/RXR function and triggers dyslipidemia in acute promyelocytic leukemia. Theranostics. 2020 Aug 15;10(22):10326-10340. doi: 10.7150/thno.45924. eCollection 2020.