Details of the Drug Combination

General Information of Drug Combination (ID: DCKWQO1)

• Drug Combination Name: Levobupivacaine + Fentanyl
• Indication: Epidural Analgesia; Status: Phase 4 [1]
• Component Drugs:
  Levobupivacaine (DM783CH): Small molecular drug
  Fentanyl (DM8WAHT): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Levobupivacaine

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

Levobupivacaine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Sodium channel unspecific (NaC)	TTRK8B9	NOUNIPROTAC	Blocker	[8]

Levobupivacaine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[9]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[10]

Indication(s) of Fentanyl

Disease Entry	ICD 11	Status	REF
Analgesia	MB40.8	Approved	[3]
Traumatic brain injury	NA07.Z	Approved	[4]
Cancer related pain	MG30	Phase 3	[5]
Pain	MG30-MG3Z	Phase 3	[6]
Chronic pain	MG30	Phase 1	[7]

Fentanyl Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Opioid receptor mu (MOP)	TTKWM86	OPRM_HUMAN	Modulator	[11]

Fentanyl Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[12]

Fentanyl Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[13]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[14]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[15]

Fentanyl Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Transport	[16]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Increases Phosphorylation	[17]
Phospholipase D2 (PLD2)	OT86I3WH	PLD2_HUMAN	Increases Activity	[18]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Decreases Expression	[19]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Increases Expression	[18]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Increases Expression	[20]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[18]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[18]
Beta-arrestin-2 (ARRB2)	OTAEJZCI	ARRB2_HUMAN	Affects Localization	[21]
Interleukin-2 (IL2)	OTGI4NSA	IL2_HUMAN	Decreases Expression	[18]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[22]
Opioid growth factor receptor (OGFR)	OTROS6RJ	OGFR_HUMAN	Increases ADR	[23]
Adenylate cyclase type 1 (ADCY1)	OTSLLFZO	ADCY1_HUMAN	Increases ADR	[23]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Anesthesia	DCR3QSU	N. A.	Phase 2	[24]

References

• [1] ClinicalTrials.gov (NCT04397406) Dexmedetomidine or Fentanyl as Additives to Epidural Levobupivacaine in Painless Labor
• [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: 7211).
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] Fentanyl FDA Label
• [5] ClinicalTrials.gov (NCT00822614) Safety of Fentanyl TAIFUN Treatment. U.S. National Institutes of Health.
• [6] A Phase III study to assess the clinical utility of low-dose fentanyl transdermal system in patients with chronic nonmalignant pain. Curr Med Res Opin. 2006 Aug;22(8):1493-501.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Block of neuronal tetrodotoxin-resistant Na+ currents by stereoisomers of piperidine local anesthetics. Anesth Analg. 2000 Dec;91(6):1499-505.
• [9] Clinical profile of levobupivacaine in regional anesthesia: A systematic review. J Anaesthesiol Clin Pharmacol. 2013 Oct;29(4):530-9.
• [10] Pharmacokinetics of levobupivacaine after caudal epidural administration in infants less than 3 months of age. Br J Anaesth. 2005 Oct;95(4):524-9.
• [11] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [12] Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
• [13] Three-dimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates. J Pharmacol Exp Ther. 1999 Oct;291(1):424-33.
• [14] Pharmacogenomics as molecular autopsy for forensic toxicology: genotyping cytochrome P450 3A4*1B and 3A5*3 for 25 fentanyl cases. J Anal Toxicol. 2005 Oct;29(7):590-8.
• [15] Drug Interactions Flockhart Table
• [16] P-Glycoprotein on Blood-Brain Barrier Plays a Vital Role in Fentanyl Brain Exposure and Respiratory Toxicity in Rats. Toxicol Sci. 2018 Jul 1;164(1):353-362. doi: 10.1093/toxsci/kfy093.
• [17] A G protein-biased ligand at the ?-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther. 2013 Mar;344(3):708-17.
• [18] opioid receptor agonist-selective regulation of interleukin-4 in T lymphocytes. J Neuroimmunol. 2013 Oct 15;263(1-2):35-42. doi: 10.1016/j.jneuroim.2013.07.012. Epub 2013 Jul 25.
• [19] Serum beta-endorphin response to stress before and after operation under fentanyl anesthesia in neonates, infants and preschool children. Eur J Pediatr Surg. 2010 Mar;20(2):106-10. doi: 10.1055/s-0029-1243620. Epub 2010 Jan 18.
• [20] Mechanisms of the inhibition of nuclear factor-B by morphine in neuronal cells. Mol Pharmacol. 2012 Apr;81(4):587-97. doi: 10.1124/mol.111.076620. Epub 2012 Jan 18.
• [21] Functional and structural characterization of axonal opioid receptors as targets for analgesia. Mol Pain. 2016 Mar 1;12:1744806916628734. doi: 10.1177/1744806916628734. Print 2016.
• [22] Why are most phospholipidosis inducers also hERG blockers?. Arch Toxicol. 2017 Dec;91(12):3885-3895. doi: 10.1007/s00204-017-1995-9. Epub 2017 May 27.
• [23] 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.
• [24] ClinicalTrials.gov (NCT02430090) Comparison of Intratechal Levobupivacaine and Adding With Sufetanil and Fentanyl in Ceserean Section