Details of the Drug Combination

General Information of Drug Combination (ID: DCNO8W3)

• Drug Combination Name: Fentanyl + Labetalol
• Indication: Laparoscopic Surgery; Status: Phase 1 [1]
• Component Drugs:
  Fentanyl (DM8WAHT): Small molecular drug
  Labetalol (DMK8U72): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Fentanyl

Disease Entry	ICD 11	Status	REF
Analgesia	MB40.8	Approved	[2]
Traumatic brain injury	NA07.Z	Approved	[3]
Cancer related pain	MG30	Phase 3	[4]
Pain	MG30-MG3Z	Phase 3	[5]
Chronic pain	MG30	Phase 1	[6]

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	[9]

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	[10]

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	[11]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[12]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[13]

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	[14]
Mu-type opioid receptor (OPRM1)	OT16AAT8	OPRM_HUMAN	Increases Phosphorylation	[15]
Phospholipase D2 (PLD2)	OT86I3WH	PLD2_HUMAN	Increases Activity	[16]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Decreases Expression	[17]
Interleukin-4 (IL4)	OTOXBWAU	IL4_HUMAN	Increases Expression	[16]
NF-kappa-B inhibitor alpha (NFKBIA)	OTFT924M	IKBA_HUMAN	Increases Expression	[18]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Increases Phosphorylation	[16]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Increases Phosphorylation	[16]
Beta-arrestin-2 (ARRB2)	OTAEJZCI	ARRB2_HUMAN	Affects Localization	[19]
Interleukin-2 (IL2)	OTGI4NSA	IL2_HUMAN	Decreases Expression	[16]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[20]
Opioid growth factor receptor (OGFR)	OTROS6RJ	OGFR_HUMAN	Increases ADR	[21]
Adenylate cyclase type 1 (ADCY1)	OTSLLFZO	ADCY1_HUMAN	Increases ADR	[21]

Indication(s) of Labetalol

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[7]
Hypertension, pregnancy-induced	N.A.	Approved	[8]
Malignant essential hypertension	BA00	Approved	[8]

Labetalol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor Alpha-1 (ADRA1)	TTG28O6	NOUNIPROTAC	Antagonist	[22]

Labetalol Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[23]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[24]

Labetalol Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[25]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[26]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[13]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[25]
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_HUMAN	Metabolism	[25]
UDP-glucuronosyltransferase 2B4 (UGT2B4)	DENUPDX	UD2B4_HUMAN	Metabolism	[25]

Labetalol Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases ADR	[21]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Activity	[27]
Angiotensinogen (AGT)	OTBZLYR3	ANGT_HUMAN	Decreases Expression	[28]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Decreases Activity	[27]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[29]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Decreases Activity	[30]
Beta-1 adrenergic receptor (ADRB1)	OTQBWN4U	ADRB1_HUMAN	Decreases Activity	[30]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Activity	[31]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Increases Activity	[32]

References

• [1] ClinicalTrials.gov (NCT01114971) Labetalol and Esmolol: Vital Signs and Post Operative Pain Management
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Fentanyl FDA Label
• [4] ClinicalTrials.gov (NCT00822614) Safety of Fentanyl TAIFUN Treatment. U.S. National Institutes of Health.
• [5] 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.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] 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: 7207).
• [8] Labetalol FDA Label
• [9] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
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• [21] 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.
• [22] Beta-blockers in the treatment of hypertension: are there clinically relevant differences Postgrad Med. 2009 May;121(3):90-8.
• [23] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [24] Involvement of influx and efflux transport systems in gastrointestinal absorption of celiprolol. J Pharm Sci. 2009 Jul;98(7):2529-39.
• [25] Regulation of UDP-glucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination. Xenobiotica. 2008 Jan;38(1):62-75.
• [26] Comparison of verapamil, diltiazem, and labetalol on the bioavailability and metabolism of imipramine. J Clin Pharmacol. 1992 Feb;32(2):176-83.
• [27] Hemodynamic and humoral effects of intravenous dilevalol in patients with moderate hypertension. Am J Cardiol. 1989 Jun 5;63(19):34I-37I. doi: 10.1016/0002-9149(89)90126-4.
• [28] Labetalol (AH5158), a competitive alpha- and beta-receptor blocking drug, in the management of hypertension. Aust N Z J Med. 1976 Aug;6(3 Suppl):83-8. doi: 10.1111/j.1445-5994.1976.tb03341.x.
• [29] Prolactin stimulation by intravenous labetalol is mediated inside the central nervous system. Clin Endocrinol (Oxf). 1982 Jun;16(6):615-9. doi: 10.1111/j.1365-2265.1982.tb03178.x.
• [30] Preclinical pharmacologic properties of dilevalol, an antihypertensive agent possessing selective beta 2 agonist-mediated vasodilation and beta antagonism. Am J Cardiol. 1989 Jun 5;63(19):3I-6I. doi: 10.1016/0002-9149(89)90120-3.
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• [32] Prediction of off-target effects on angiotensin-converting enzyme 2. J Biomol Screen. 2011 Sep;16(8):878-85. doi: 10.1177/1087057111413919. Epub 2011 Aug 22.