General Information of Drug Combination (ID: DCMUMUW)

Drug Combination Name
Ritonavir MK-4815
Indication
Disease Entry Status REF
Hepatoblastoma Investigative [1]
Component Drugs Ritonavir   DMU764S MK-4815   DMT9K74
Small molecular drug N.A.
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: HB3
Zero Interaction Potency (ZIP) Score: 10.142
Bliss Independence Score: 16.139
Loewe Additivity Score: 1.51
LHighest Single Agent (HSA) Score: 4.135

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Ritonavir
Disease Entry ICD 11 Status REF
Human immunodeficiency virus infection 1C62 Approved [2]
Ritonavir 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 Inhibitor [6]
------------------------------------------------------------------------------------
Ritonavir Interacts with 3 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
Multidrug resistance-associated protein 2 (ABCC2) DTFI42L MRP2_HUMAN Substrate [7]
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [8]
Organic anion transporting polypeptide 2B1 (SLCO2B1) DTPFTEQ SO2B1_HUMAN Substrate [9]
------------------------------------------------------------------------------------
Ritonavir Interacts with 5 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [10]
Cytochrome P450 2D6 (CYP2D6) DECB0K3 CP2D6_HUMAN Metabolism [11]
Cytochrome P450 3A5 (CYP3A5) DEIBDNY CP3A5_HUMAN Metabolism [12]
Cytochrome P450 3A7 (CYP3A7) DERD86B CP3A7_HUMAN Metabolism [10]
Cytochrome P450 2B6 (CYP2B6) DEPKLMQ CP2B6_HUMAN Metabolism [13]
------------------------------------------------------------------------------------
Ritonavir Interacts with 90 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Cytochrome P450 3A5 (CYP3A5) OTSXFBXB CP3A5_HUMAN Decreases Activity [14]
Cytochrome P450 2B6 (CYP2B6) OTOYO4S7 CP2B6_HUMAN Increases Activity [15]
Cytochrome P450 3A4 (CYP3A4) OTQGYY83 CP3A4_HUMAN Increases Expression [16]
Adiponectin (ADIPOQ) OTNX23LE ADIPO_HUMAN Decreases Expression [17]
Sterol regulatory element-binding protein 2 (SREBF2) OTBXUNPL SRBP2_HUMAN Increases ADR [18]
Sterol regulatory element-binding protein 1 (SREBF1) OTWBRPAI SRBP1_HUMAN Increases ADR [18]
Cytochrome P450 1A1 (CYP1A1) OTE4EFH8 CP1A1_HUMAN Increases Expression [19]
Cytochrome P450 1A2 (CYP1A2) OTLLBX48 CP1A2_HUMAN Increases Expression [19]
Cytochrome P450 2C9 (CYP2C9) OTGLBN29 CP2C9_HUMAN Increases Expression [19]
Cytochrome P450 2C19 (CYP2C19) OTFMJYYE CP2CJ_HUMAN Increases Expression [19]
Cytochrome P450 2C8 (CYP2C8) OTHCWT42 CP2C8_HUMAN Decreases Activity [20]
Bile salt export pump (ABCB11) OTRU7THO ABCBB_HUMAN Decreases Activity [21]
Fibroblast growth factor 19 (FGF19) OT2DVJWY FGF19_HUMAN Increases Expression [15]
C-X-C motif chemokine 10 (CXCL10) OTTLQ6S0 CXL10_HUMAN Decreases Expression [15]
Growth-regulated alpha protein (CXCL1) OT3WCTZV GROA_HUMAN Decreases Expression [15]
Interleukin-7 (IL7) OTT6YSKM IL7_HUMAN Decreases Expression [15]
C-C motif chemokine 4 (CCL4) OT6B8P25 CCL4_HUMAN Decreases Expression [15]
Leukemia inhibitory factor (LIF) OTO46S5S LIF_HUMAN Decreases Expression [15]
C-X-C motif chemokine 2 (CXCL2) OTEJCYMY CXCL2_HUMAN Decreases Expression [15]
Sterol carrier protein 2 (SCP2) OTPAFCPQ SCP2_HUMAN Decreases Expression [15]
Cytochrome P450 7A1 (CYP7A1) OT8Z5KLD CP7A1_HUMAN Decreases Expression [15]
Interleukin-32 (IL32) OT3FHZ81 IL32_HUMAN Decreases Expression [15]
MHC class II transactivator (CIITA) OTRJNZFO C2TA_HUMAN Increases Expression [15]
C-X-C motif chemokine 5 (CXCL5) OTZOUPCA CXCL5_HUMAN Decreases Expression [15]
Stromal cell-derived factor 1 (CXCL12) OT2QX5LL SDF1_HUMAN Decreases Expression [15]
C-C motif chemokine 20 (CCL20) OTUCJY4N CCL20_HUMAN Decreases Expression [15]
C-X-C motif chemokine 6 (CXCL6) OTFTCQ4O CXCL6_HUMAN Decreases Expression [15]
Hepatic sodium/bile acid cotransporter (SLC10A1) OTUJVMCL NTCP_HUMAN Decreases Expression [15]
Organic solute transporter subunit alpha (SLC51A) OTDJRZ0P OSTA_HUMAN Decreases Expression [15]
Protein NLRC5 (NLRC5) OTY8X6MC NLRC5_HUMAN Decreases Expression [15]
Heat shock protein 105 kDa (HSPH1) OTVRR73T HS105_HUMAN Increases Expression [15]
Bile acid receptor (NR1H4) OTWZLPTB NR1H4_HUMAN Increases Expression [15]
7-alpha-hydroxycholest-4-en-3-one 12-alpha-hydroxylase (CYP8B1) OTRI4UR1 CP8B1_HUMAN Decreases Expression [15]
Transcription factor E2F3 (E2F3) OT5VQMWY E2F3_HUMAN Decreases Expression [22]
Baculoviral IAP repeat-containing protein 5 (BIRC5) OTILXZYL BIRC5_HUMAN Decreases Expression [23]
G1/S-specific cyclin-E2 (CCNE2) OTBBUKQQ CCNE2_HUMAN Decreases Expression [22]
Protein c-Fos (FOS) OTJBUVWS FOS_HUMAN Increases Expression [24]
Myc proto-oncogene protein (MYC) OTPV5LUK MYC_HUMAN Decreases Expression [23]
Tumor necrosis factor (TNF) OT4IE164 TNFA_HUMAN Decreases Secretion [25]
Prelamin-A/C (LMNA) OT3SG7ZR LMNA_HUMAN Increases Expression [26]
Albumin (ALB) OTVMM513 ALBU_HUMAN Affects Binding [27]
Estrogen receptor (ESR1) OTKLU61J ESR1_HUMAN Decreases Expression [28]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Increases Expression [22]
Interleukin-6 (IL6) OTUOSCCU IL6_HUMAN Increases Expression [17]
Intercellular adhesion molecule 1 (ICAM1) OTTOIX77 ICAM1_HUMAN Increases Expression [29]
Transcription factor Jun (JUN) OTCYBO6X JUN_HUMAN Increases Expression [24]
Retinoblastoma-associated protein (RB1) OTQJUJMZ RB_HUMAN Increases Expression [22]
Heme oxygenase 1 (HMOX1) OTC1W6UX HMOX1_HUMAN Increases Expression [24]
Poly polymerase 1 (PARP1) OT310QSG PARP1_HUMAN Increases Cleavage [22]
Interleukin-8 (CXCL8) OTS7T5VH IL8_HUMAN Increases Secretion [26]
C-C motif chemokine 3 (CCL3) OTW2H3ND CCL3_HUMAN Increases Expression [17]
Apoptosis regulator Bcl-2 (BCL2) OT9DVHC0 BCL2_HUMAN Decreases Expression [22]
Cyclin-dependent kinase 4 (CDK4) OT7EP05T CDK4_HUMAN Decreases Expression [22]
Proto-oncogene tyrosine-protein kinase Src (SRC) OTETYX40 SRC_HUMAN Decreases Phosphorylation [30]
C-C motif chemokine 2 (CCL2) OTAD2HEL CCL2_HUMAN Increases Expression [17]
G2/mitotic-specific cyclin-B1 (CCNB1) OT19S7E5 CCNB1_HUMAN Decreases Expression [22]
Beta-galactosidase (GLB1) OTB0TKAG BGAL_HUMAN Increases Activity [26]
Nuclear factor NF-kappa-B p105 subunit (NFKB1) OTNRRD8I NFKB1_HUMAN Decreases Activity [23]
Cyclin-A2 (CCNA2) OTPHHYZJ CCNA2_HUMAN Decreases Expression [22]
Phosphatidylcholine translocator ABCB4 (ABCB4) OTE6PY83 MDR3_HUMAN Decreases Activity [31]
G1/S-specific cyclin-D1 (CCND1) OT8HPTKJ CCND1_HUMAN Decreases Expression [28]
Cyclin-dependent kinase 2 (CDK2) OTB5DYYZ CDK2_HUMAN Decreases Expression [22]
NF-kappa-B inhibitor alpha (NFKBIA) OTFT924M IKBA_HUMAN Decreases Phosphorylation [23]
Retinoblastoma-like protein 1 (RBL1) OTDEBFYC RBL1_HUMAN Increases Expression [22]
Caspase-1 (CASP1) OTZ3YQFU CASP1_HUMAN Decreases Expression [25]
Nitric oxide synthase 3 (NOS3) OTLDT7NR NOS3_HUMAN Decreases Expression [32]
G1/S-specific cyclin-D2 (CCND2) OTDULQF9 CCND2_HUMAN Decreases Expression [23]
Peroxisome proliferator-activated receptor gamma (PPARG) OTHMARHO PPARG_HUMAN Increases Expression [33]
Cyclin-dependent kinase inhibitor 1 (CDKN1A) OTQWHCZE CDN1A_HUMAN Increases Expression [22]
Signal transducer and activator of transcription 3 (STAT3) OTAAGKYZ STAT3_HUMAN Decreases Phosphorylation [30]
Leptin (LEP) OT5Q7ODW LEP_HUMAN Decreases Expression [17]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Decreases Activity [25]
Cyclin-dependent kinase 4 inhibitor B (CDKN2B) OTAG24N1 CDN2B_HUMAN Increases Expression [22]
Cyclin-dependent kinase inhibitor 1B (CDKN1B) OTNY5LLZ CDN1B_HUMAN Increases Expression [22]
Tumor necrosis factor ligand superfamily member 6 (FASLG) OTZARCHH TNFL6_HUMAN Decreases Expression [25]
Cyclin-dependent kinase 3 (CDK3) OT2GP6RL CDK3_HUMAN Increases Expression [22]
Cyclin-dependent kinase 6 (CDK6) OTR95N0X CDK6_HUMAN Decreases Expression [22]
Cyclin-dependent kinase 5 (CDK5) OT1YAK9F CDK5_HUMAN Decreases Expression [22]
Transcription factor E2F1 (E2F1) OTLKYBBC E2F1_HUMAN Decreases Expression [22]
Transcription factor p65 (RELA) OTUJP9CN TF65_HUMAN Decreases Activity [23]
Proto-oncogene c-Rel (REL) OTTCKMAC REL_HUMAN Decreases Activity [23]
Bcl-2-like protein 1 (BCL2L1) OTRC5K9O B2CL1_HUMAN Decreases Expression [23]
Retinoblastoma-like protein 2 (RBL2) OTBQSOE6 RBL2_HUMAN Decreases Expression [22]
Transcription factor E2F2 (E2F2) OTO75RM7 E2F2_HUMAN Decreases Expression [22]
Nuclear factor erythroid 2-related factor 2 (NFE2L2) OT0HENJ5 NF2L2_HUMAN Increases Expression [29]
Bcl-2 homologous antagonist/killer (BAK1) OTDP6ILW BAK_HUMAN Increases Expression [22]
Cytochrome P450 1B1 (CYP1B1) OTYXFLSD CP1B1_HUMAN Decreases Activity [34]
Scavenger receptor class B member 1 (SCARB1) OTAE1UA1 SCRB1_HUMAN Increases Expression [33]
AP-2 complex subunit alpha-2 (AP2A2) OTD1UGUN AP2A2_HUMAN Increases ADR [18]
Lipoprotein lipase (LPL) OTTW0267 LIPL_HUMAN Increases ADR [18]
------------------------------------------------------------------------------------
⏷ Show the Full List of 90 DOT(s)
Indication(s) of MK-4815
Disease Entry ICD 11 Status REF
Malaria 1F40-1F45 Investigative [3]

Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
DD2 DC3MXAG DD2 Investigative [1]
------------------------------------------------------------------------------------

References

1 Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
2 Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
3 The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
4 A potent HIV protease inhibitor, darunavir, does not inhibit ZMPSTE24 or lead to an accumulation of farnesyl-prelamin A in cells. J Biol Chem. 2008 Apr 11;283(15):9797-804. doi: 10.1074/jbc.M709629200. Epub 2008 Jan 28.
5 Modulation of UDP-glucuronosyltransferase 1A1 in primary human hepatocytes by prototypical inducers. J Biochem Mol Toxicol. 2005;19(2):96-108. doi: 10.1002/jbt.20058.
6 Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV. Int J Antimicrob Agents. 2009 Apr;33(4):307-20.
7 Interaction of eight HIV protease inhibitors with the canalicular efflux transporter ABCC2 (MRP2) in sandwich-cultured rat and human hepatocytes. Biopharm Drug Dispos. 2010 Mar;31(2-3):178-88.
8 MDR1 G1199A polymorphism alters permeability of HIV protease inhibitors across P-glycoprotein-expressing epithelial cells. AIDS. 2005 Oct 14;19(15):1617-25.
9 pH dependence of organic anion-transporting polypeptide 2B1 in Caco-2 cells: potential role in antiretroviral drug oral bioavailability and drug-drug interactions. J Pharmacol Exp Ther. 2010 Sep 1;334(3):1009-22.
10 Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: comparison with ritonavir. Clin Pharmacol Ther. 2006 Mar;79(3):243-54.
11 Reversible coma caused by risperidone-ritonavir interaction. Clin Neuropharmacol. 2002 Sep-Oct;25(5):251-3.
12 Drug Interactions Flockhart Table
13 Evaluation of CYP2B6 induction and prediction of clinical drug-drug interactions: considerations from the IQ consortium induction working group-an industry perspective. Drug Metab Dispos. 2016 Oct;44(10):1720-30.
14 Mechanism-based inactivation of CYP3A by HIV protease inhibitors. J Pharmacol Exp Ther. 2005 Feb;312(2):583-91.
15 Transcriptional profiling suggests that Nevirapine and Ritonavir cause drug induced liver injury through distinct mechanisms in primary human hepatocytes. Chem Biol Interact. 2016 Aug 5;255:31-44.
16 Use of immortalized human hepatocytes to predict the magnitude of clinical drug-drug interactions caused by CYP3A4 induction. Drug Metab Dispos. 2006 Oct;34(10):1742-8.
17 Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir Ther. 2007;12(4):489-500.
18 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.
19 Severe interaction between ritonavir and acenocoumarol. Ann Pharmacother. 2002 Apr;36(4):621-3.
20 Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol. 2005 Jan;45(1):68-78.
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 Ritonavir blocks AKT signaling, activates apoptosis and inhibits migration and invasion in ovarian cancer cells. Mol Cancer. 2009 Apr 22;8:26. doi: 10.1186/1476-4598-8-26.
23 Efficient intervention of growth and infiltration of primary adult T-cell leukemia cells by an HIV protease inhibitor, ritonavir. Blood. 2006 Jan 15;107(2):716-24. doi: 10.1182/blood-2005-02-0735. Epub 2005 Sep 20.
24 The HIV protease inhibitor ritonavir synergizes with butyrate for induction of apoptotic cell death and mediates expression of heme oxygenase-1 in DLD-1 colon carcinoma cells. Br J Pharmacol. 2004 Dec;143(7):890-8. doi: 10.1038/sj.bjp.0706023. Epub 2004 Oct 25.
25 HIV-1 protease inhibitor ritonavir modulates susceptibility to apoptosis of uninfected T cells. J Hum Virol. 1999 Sep-Oct;2(5):261-9.
26 Premature senescence of vascular cells is induced by HIV protease inhibitors: implication of prelamin A and reversion by statin. Arterioscler Thromb Vasc Biol. 2010 Dec;30(12):2611-20. doi: 10.1161/ATVBAHA.110.213603. Epub 2010 Sep 30.
27 Binding of anti-HIV drugs to human serum albumin. IUBMB Life. 2004 Oct;56(10):609-14. doi: 10.1080/15216540400016286.
28 Effects of HIV protease inhibitor ritonavir on Akt-regulated cell proliferation in breast cancer. Clin Cancer Res. 2006 Mar 15;12(6):1883-96. doi: 10.1158/1078-0432.CCR-05-1167.
29 Heme oxygenase-1-derived bilirubin counteracts HIV protease inhibitor-mediated endothelial cell dysfunction. Free Radic Biol Med. 2016 May;94:218-29. doi: 10.1016/j.freeradbiomed.2016.03.003. Epub 2016 Mar 8.
30 The human immunodeficiency virus protease inhibitor ritonavir inhibits lung cancer cells, in part, by inhibition of survivin. J Thorac Oncol. 2011 Apr;6(4):661-70. doi: 10.1097/JTO.0b013e31820c9e3c.
31 Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals. Chem Res Toxicol. 2017 May 15;30(5):1219-1229. doi: 10.1021/acs.chemrestox.7b00048. Epub 2017 May 4.
32 Nordihydroguaiaretic acid (NDGA) inhibits ritonavir-induced endothelial dysfunction in porcine pulmonary arteries. Med Sci Monit. 2011 Nov;17(11):BR312-318. doi: 10.12659/msm.882040.
33 Estrogen prevents cholesteryl ester accumulation in macrophages induced by the HIV protease inhibitor ritonavir. J Cell Biochem. 2008 Apr 1;103(5):1598-606. doi: 10.1002/jcb.21546.
34 Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.