Details of the Drug Combination

General Information of Drug Combination (ID: DCZFAHD)

• Drug Combination Name: Isoflurane + Sevoflurane
• Indication: Delirium on Emergence; Status: Phase 4 [1]
• Component Drugs:
  Isoflurane (DMY6T31): Small molecular drug
  Sevoflurane (DMC9O43): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Isoflurane

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[2]

Isoflurane Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Glutamate receptor AMPA (GRIA)	TTAN6JD	NOUNIPROTAC	Agonist	[5]

Isoflurane Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[6]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[7]

Isoflurane Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Renin (REN)	OT52GZR2	RENI_HUMAN	Affects Activity	[8]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[9]
Beta-secretase 1 (BACE1)	OTCA7B6A	BACE1_HUMAN	Increases Expression	[10]
Nicastrin (NCSTN)	OT5QBTA4	NICA_HUMAN	Increases Expression	[10]

Indication(s) of Sevoflurane

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[4]

Sevoflurane Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Glutamate receptor AMPA (GRIA)	TTAN6JD	NOUNIPROTAC	Antagonist	[11]

Sevoflurane Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[12]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[13]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[14]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[7]

Sevoflurane Interacts with 60 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Expression	[15]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[16]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[16]
Glycine receptor subunit alpha-1 (GLRA1)	OT05Y9ZR	GLRA1_HUMAN	Increases ADR	[17]
Glutamate dehydrogenase 1, mitochondrial (GLUD1)	OTXKOCUH	DHE3_HUMAN	Increases Expression	[18]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Increases Expression	[19]
GTPase HRas (HRAS)	OTWQN0DP	RASH_HUMAN	Increases Expression	[19]
GTPase KRas (KRAS)	OT78QCN8	RASK_HUMAN	Decreases Expression	[19]
Progonadoliberin-1 (GNRH1)	OTH8A44K	GON1_HUMAN	Increases Expression	[19]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[19]
Fibronectin (FN1)	OTB5ZN4Q	FINC_HUMAN	Increases Expression	[19]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Increases Expression	[15]
Insulin-like growth factor I (IGF1)	OTIIZR61	IGF1_HUMAN	Increases Expression	[19]
Amyloid-beta precursor protein (APP)	OTKFD7R4	A4_HUMAN	Increases Expression	[20]
Integrin beta-3 (ITGB3)	OTWCK1K6	ITB3_HUMAN	Decreases Expression	[19]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[19]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1)	OTA675TJ	GTR1_HUMAN	Increases Expression	[18]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Decreases Expression	[19]
Proto-oncogene tyrosine-protein kinase Src (SRC)	OTETYX40	SRC_HUMAN	Increases Expression	[19]
Hepatocyte growth factor (HGF)	OTGHUA23	HGF_HUMAN	Increases Expression	[19]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Increases Expression	[19]
Cyclic AMP-dependent transcription factor ATF-2 (ATF2)	OTNIZPEA	ATF2_HUMAN	Increases Phosphorylation	[9]
Sphingomyelin phosphodiesterase (SMPD1)	OTZSMA54	ASM_HUMAN	Decreases Activity	[15]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[18]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[18]
Ephrin type-B receptor 2 (EPHB2)	OT8VZ6C5	EPHB2_HUMAN	Increases Expression	[19]
Macrosialin (CD68)	OTOYEY3J	CD68_HUMAN	Increases Expression	[19]
Merlin (NF2)	OT6E5ACG	MERL_HUMAN	Increases Expression	[19]
Pigment epithelium-derived factor (SERPINF1)	OTWZH98J	PEDF_HUMAN	Decreases Expression	[18]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Phosphorylation	[16]
Cell surface glycoprotein MUC18 (MCAM)	OTT8XKGE	MUC18_HUMAN	Decreases Expression	[19]
Collagenase 3 (MMP13)	OTY8BZIE	MMP13_HUMAN	Increases Expression	[19]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Increases Expression	[18]
Dual specificity mitogen-activated protein kinase kinase 3 (MAP2K3)	OTI2OREX	MP2K3_HUMAN	Increases Phosphorylation	[9]
Stromal cell-derived factor 1 (CXCL12)	OT2QX5LL	SDF1_HUMAN	Increases Expression	[18]
Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6)	OTK13JKC	MP2K6_HUMAN	Increases Phosphorylation	[9]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[21]
Beta-secretase 1 (BACE1)	OTCA7B6A	BACE1_HUMAN	Increases Expression	[20]
C-X-C chemokine receptor type 4 (CXCR4)	OTUFSBX2	CXCR4_HUMAN	Increases Expression	[18]
Protein SET (SET)	OTGYYQJO	SET_HUMAN	Increases Expression	[19]
RNA-binding protein EWS (EWSR1)	OT7SRHV3	EWS_HUMAN	Increases Expression	[19]
Urokinase plasminogen activator surface receptor (PLAUR)	OTIRKKEQ	UPAR_HUMAN	Increases Expression	[19]
Alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase A (MGAT5)	OTU4DD4G	MGT5A_HUMAN	Increases Expression	[19]
Metastasis-associated protein MTA1 (MTA1)	OTBHW3S9	MTA1_HUMAN	Increases Expression	[19]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Decreases Expression	[16]
Integrin alpha-7 (ITGA7)	OTTBTAYW	ITA7_HUMAN	Decreases Expression	[19]
Interleukin-18 (IL18)	OTBB2A8O	IL18_HUMAN	Increases Expression	[19]
Metastasis-suppressor KiSS-1 (KISS1)	OT6IE3K2	KISS1_HUMAN	Decreases Expression	[19]
Mothers against decapentaplegic homolog 2 (SMAD2)	OTC6VB4K	SMAD2_HUMAN	Increases Expression	[19]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Increases Expression	[19]
KiSS-1 receptor (KISS1R)	OTQA3J6G	KISSR_HUMAN	Decreases Expression	[19]
FXYD domain-containing ion transport regulator 5 (FXYD5)	OT81DIOD	FXYD5_HUMAN	Increases Expression	[19]
Mitogen-activated protein kinase kinase kinase 5 (MAP3K5)	OTQR6ENW	M3K5_HUMAN	Increases Phosphorylation	[9]
Oxidoreductase HTATIP2 (HTATIP2)	OT9MZ4QO	HTAI2_HUMAN	Increases Expression	[19]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Lipidation	[16]
Autophagy protein 5 (ATG5)	OT4T5SMS	ATG5_HUMAN	Increases Expression	[16]
Pinin (PNN)	OT0HXICH	PININ_HUMAN	Increases Expression	[19]
Programmed cell death 1 ligand 1 (CD274)	OTJ0VFDL	PD1L1_HUMAN	Decreases Expression	[22]
Heparanase (HPSE)	OTPTK5VS	HPSE_HUMAN	Increases Expression	[19]
Mitochondrial pyruvate carrier 1 (MPC1)	OT6DYFUO	MPC1_HUMAN	Increases Expression	[18]

References

• [1] ClinicalTrials.gov (NCT02111447) Post Anesthesia Emergence and Behavioral Changes in Children Undergoing MRI
• [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: 2505).
• [3] 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: 7296).
• [4] Sevoflurane in COVID-19 ARDS (SevCov)
• [5] Transmembrane residues define the action of isoflurane at the GABAA receptor alpha-3 subunit. Brain Res. 2005 Jan 25;1032(1-2):30-5.
• [6] Clinical isoflurane metabolism by cytochrome P450 2E1. Anesthesiology. 1999 Mar;90(3):766-71.
• [7] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [8] The stress response to induced hypotension for cerebral aneurysm surgery: a comparison of two hypotensive techniques. Can J Anaesth. 1988 Mar;35(2):111-5. doi: 10.1007/BF03010648.
• [9] Sevoflurane-mediated activation of p38-mitogen-activated stresskinase is independent of apoptosis in Jurkat T-cells. Anesth Analg. 2008 Apr;106(4):1150-60, table of contents. doi: 10.1213/ane.0b013e3181683d37.
• [10] The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and amyloid beta-protein accumulation. J Neurosci. 2007 Feb 7;27(6):1247-54. doi: 10.1523/JNEUROSCI.5320-06.2007.
• [11] Effects of sevoflurane on carrageenan- and fentanyl-induced pain hypersensitivity in Sprague-Dawley rats. Can J Anaesth. 2009 Feb;56(2):126-35.
• [12] Identification of cytochrome P450 2E1 as the predominant enzyme catalyzing human liver microsomal defluorination of sevoflurane, isoflurane, and methoxyflurane. Anesthesiology. 1993 Oct;79(4):795-807.
• [13] Human kidney methoxyflurane and sevoflurane metabolism. Intrarenal fluoride production as a possible mechanism of methoxyflurane nephrotoxicity. Anesthesiology. 1995 Mar;82(3):689-99.
• [14] Inhibition of cytochrome P450 2E1 by propofol in human and porcine liver microsomes. Biochem Pharmacol. 2002 Oct 1;64(7):1151-6.
• [15] Different apoptosis ratios and gene expressions in two human cell lines after sevoflurane anaesthesia. Acta Anaesthesiol Scand. 2009 Oct;53(9):1192-9. doi: 10.1111/j.1399-6576.2009.02036.x. Epub 2009 Jun 30.
• [16] 4.8% sevoflurane induces activation of autophagy in human neuroblastoma SH-SY5Y cells by the AMPK/mTOR signaling pathway. Neurotoxicology. 2022 May;90:256-264. doi: 10.1016/j.neuro.2022.04.008. Epub 2022 Apr 23.
• [17] 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.
• [18] Sevoflurane but not propofol enhances ovarian cancer cell biology through regulating cellular metabolic and signaling mechanisms. Cell Biol Toxicol. 2023 Aug;39(4):1395-1411. doi: 10.1007/s10565-022-09766-6. Epub 2022 Oct 8.
• [19] The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence. Cell Biol Toxicol. 2023 Aug;39(4):1561-1575. doi: 10.1007/s10565-022-09747-9. Epub 2022 Aug 12.
• [20] The common inhalational anesthetic sevoflurane induces apoptosis and increases beta-amyloid protein levels. Arch Neurol. 2009 May;66(5):620-31. doi: 10.1001/archneurol.2009.48.
• [21] Sevoflurane-induced oxidative stress and cellular injury in human peripheral polymorphonuclear neutrophils. Food Chem Toxicol. 2006 Aug;44(8):1399-407. doi: 10.1016/j.fct.2006.03.004. Epub 2006 Mar 29.
• [22] CircRNA VIM silence synergizes with sevoflurane to inhibit immune escape and multiple oncogenic activities of esophageal cancer by simultaneously regulating miR-124/PD-L1 axis. Cell Biol Toxicol. 2022 Oct;38(5):825-845. doi: 10.1007/s10565-021-09613-0. Epub 2021 May 20.