Details of the Drug Combination

General Information of Drug Combination (ID: DCIZ4US)

• Drug Combination Name: Ketamine + Clonidine
• Indication: Postoperative Pain; Status: Phase 4 [1]
• Component Drugs:
  Ketamine (DMT5HA4): Small molecular drug
  Clonidine (DM6RZ9Q): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ketamine

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[2]
Anxiety	N.A.	Approved	[3]
Bipolar disorder	6A60	Approved	[3]
Depression	6A70-6A7Z	Approved	[3]
Traumatic brain injury	NA07.Z	Approved	[3]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2	[4]
Chronic pain	MG30	Investigative	[3]

Ketamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
N-methyl-D-aspartate receptor (NMDAR)	TT9IK2Z	NOUNIPROTAC	Antagonist	[9]

Ketamine Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[10]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[10]

Ketamine Interacts with 10 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Zinc finger protein SNAI2 (SNAI2)	OT7Y8EJ2	SNAI2_HUMAN	Increases Expression	[8]
Zinc finger protein SNAI1 (SNAI1)	OTDPYAMC	SNAI1_HUMAN	Increases Expression	[8]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Expression	[11]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases Expression	[8]
Amyloid-beta precursor protein (APP)	OTKFD7R4	A4_HUMAN	Increases Expression	[12]
Cadherin-1 (CDH1)	OTFJMXPM	CADH1_HUMAN	Decreases Expression	[8]
Protein S100-A4 (S100A4)	OTLRGFSQ	S10A4_HUMAN	Increases Expression	[8]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[13]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Increases Expression	[8]
Sodium/hydrogen exchanger 6 (SLC9A6)	OT5N47TC	SL9A6_HUMAN	Decreases Expression	[12]

Indication(s) of Clonidine

Disease Entry	ICD 11	Status	REF
Attention deficit hyperactivity disorder	6A05.Z	Approved	[5]
Hypertension	BA00-BA04	Approved	[6]
Neonatal abstinence syndrome	N.A.	Approved	[5]
Diabetic neuropathy	8C0Z	Phase 3	[7]

Clonidine Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor Alpha-2 (ADRA2)	TTQ8AFT	NOUNIPROTAC	Agonist	[14]
Membrane copper amine oxidase (AOC3)	TT7HC21	AOC3_HUMAN	Inhibitor	[15]

Clonidine Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[16]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[17]
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[17]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[17]

Clonidine Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[18]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[18]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[18]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[18]

Clonidine Interacts with 10 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
G protein-activated inward rectifier potassium channel 1 (KCNJ3)	OTHQG16J	KCNJ3_HUMAN	Increases ADR	[19]
Apoptosis-inducing factor 1, mitochondrial (AIFM1)	OTKPWB7Q	AIFM1_HUMAN	Increases Expression	[20]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Activity	[21]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Increases Expression	[22]
Tumor necrosis factor alpha-induced protein 3 (TNFAIP3)	OTVLI4DD	TNAP3_HUMAN	Increases Expression	[23]
Tumor protein D52 (TPD52)	OTPKSK43	TPD52_HUMAN	Increases Expression	[23]
Programmed cell death protein 4 (PDCD4)	OTZ6NXUX	PDCD4_HUMAN	Decreases Expression	[23]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[20]
Delta-type opioid receptor (OPRD1)	OT164PA1	OPRD_HUMAN	Increases ADR	[19]
Kappa-type opioid receptor (OPRK1)	OTXCZF4L	OPRK_HUMAN	Increases ADR	[19]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Depressive Disorder, Treatment-Resistant	DC24WFO	N. A.	Phase 1	[24]

References

• [1] ClinicalTrials.gov (NCT03124082) OFA - Opioid Free Anesthesia
• [2] FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (ANDA) 076092.
• [3] Ketamine FDA Label
• [4] ClinicalTrials.gov (NCT04365985) Study of Immunomodulation Using Naltrexone and Ketamine for COVID-19. U.S. National Institutes of Health.
• [5] Clonidine FDA Label
• [6] 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: 516).
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Ketamine-induced bladder fibrosis involves epithelial-to-mesenchymal transition mediated by transforming growth factor-1. Am J Physiol Renal Physiol. 2017 Oct 1;313(4):F961-F972. doi: 10.1152/ajprenal.00686.2016. Epub 2017 Mar 22.
• [9] Ketamine modulates theta and gamma oscillations. J Cogn Neurosci. 2010 Jul;22(7):1452-64.
• [10] Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos. 2002 Jul;30(7):853-8.
• [11] Ketamine hypertension and the renin-angiotensin system. Clin Exp Hypertens A. 1983;5(6):875-83. doi: 10.3109/10641968309081814.
• [12] Ketamine promotes the amyloidogenic pathway by regulating endosomal pH. Toxicology. 2022 Apr 15;471:153163. doi: 10.1016/j.tox.2022.153163. Epub 2022 Apr 1.
• [13] Lipoxin A4 methyl ester attenuated ketamine-induced neurotoxicity in SH-SY5Y cells via regulating leptin pathway. Toxicol In Vitro. 2023 Jun;89:105581. doi: 10.1016/j.tiv.2023.105581. Epub 2023 Mar 11.
• [14] Noradrenergic alpha-2 receptor agonists reverse working memory deficits induced by the anxiogenic drug, FG7142, in rats. Pharmacol Biochem Behav. 2000 Nov;67(3):397-403.
• [15] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [16] Caco-2 permeability, P-glycoprotein transport ratios and brain penetration of heterocyclic drugs. Int J Pharm. 2003 Sep 16;263(1-2):113-22.
• [17] Influx Transport of Cationic Drug at the Blood-Retinal Barrier: Impact on the Retinal Delivery of Neuroprotectants. Biol Pharm Bull. 2017;40(8):1139-1145.
• [18] CYP2D6 mediates 4-hydroxylation of clonidine in vitro: implication for pregnancy-induced changes in clonidine clearance. Drug Metab Dispos. 2010 Sep;38(9):1393-6.
• [19] 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.
• [20] Clonidine Induces Apoptosis of Human Corneal Epithelial Cells through Death Receptors-Mediated, Mitochondria-Dependent Signaling Pathway. Toxicol Sci. 2017 Mar 1;156(1):252-260. doi: 10.1093/toxsci/kfw249.
• [21] The effect of clonidine and penbutolol, respectively on catecholamines in blood and urine, plasma renin activity and urinary aldosterone in hypertensive patients. Arch Int Pharmacodyn Ther. 1975 Feb;213(2):307-21.
• [22] Normalization of blood pressure and plasma concentrations of beta-endorphin and leucine-enkephalin in patients with primary hypertension after treatment with clonidine. J Cardiovasc Pharmacol. 1987;10 Suppl 12:S147-51.
• [23] Human embryonic stem cell derived hepatocyte-like cells as a tool for in vitro hazard assessment of chemical carcinogenicity. Toxicol Sci. 2011 Dec;124(2):278-90. doi: 10.1093/toxsci/kfr225. Epub 2011 Aug 27.
• [24] ClinicalTrials.gov (NCT01179009) Treatment Resistant Depression (Pilot)