Details of the Drug Combination

General Information of Drug Combination (ID: DCARI40)

• Drug Combination Name: Clonidine + Levobupivacaine
• Indication: Anesthesia, Epidural; Status: Phase 3 [1]
• Component Drugs:
  Clonidine (DM6RZ9Q): Small molecular drug
  Levobupivacaine (DM783CH): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Clonidine

Disease Entry	ICD 11	Status	REF
Attention deficit hyperactivity disorder	6A05.Z	Approved	[2]
Hypertension	BA00-BA04	Approved	[3]
Neonatal abstinence syndrome	N.A.	Approved	[2]
Diabetic neuropathy	8C0Z	Phase 3	[4]

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	[6]
Membrane copper amine oxidase (AOC3)	TT7HC21	AOC3_HUMAN	Inhibitor	[7]

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	[8]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[9]
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[9]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[9]

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	[10]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[10]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[10]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[10]

Clonidine Interacts with 24 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases ADR	[11]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases ADR	[11]
G protein-activated inward rectifier potassium channel 1 (KCNJ3)	OTHQG16J	KCNJ3_HUMAN	Increases ADR	[11]
Apoptosis-inducing factor 1, mitochondrial (AIFM1)	OTKPWB7Q	AIFM1_HUMAN	Increases Expression	[12]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Activity	[13]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Increases Expression	[14]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[15]
Somatotropin (GH1)	OT92RTRD	SOMA_HUMAN	Increases Expression	[16]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Decreases Secretion	[17]
Apolipoprotein A-I (APOA1)	OT5THARI	APOA1_HUMAN	Decreases Expression	[18]
Apolipoprotein A-II (APOA2)	OTQ3HGTC	APOA2_HUMAN	Decreases Expression	[18]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[12]
Tumor necrosis factor alpha-induced protein 3 (TNFAIP3)	OTVLI4DD	TNAP3_HUMAN	Increases Expression	[19]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Secretion	[20]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[12]
Caspase-2 (CASP2)	OTUDYSPP	CASP2_HUMAN	Increases Activity	[12]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[12]
Tumor protein D52 (TPD52)	OTPKSK43	TPD52_HUMAN	Increases Expression	[19]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[12]
Programmed cell death protein 4 (PDCD4)	OTZ6NXUX	PDCD4_HUMAN	Decreases Expression	[19]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[12]
Delta-type opioid receptor (OPRD1)	OT164PA1	OPRD_HUMAN	Increases ADR	[11]
Myeloperoxidase (MPO)	OTOOXLIN	PERM_HUMAN	Increases ADR	[11]
Kappa-type opioid receptor (OPRK1)	OTXCZF4L	OPRK_HUMAN	Increases ADR	[11]

Indication(s) of Levobupivacaine

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[5]

Levobupivacaine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Sodium channel unspecific (NaC)	TTRK8B9	NOUNIPROTAC	Blocker	[21]

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	[22]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[23]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Knee Osteoarthritis	DCSSXSU	N. A.	Phase 1	[24]

References

• [1] ClinicalTrials.gov (NCT02563821) Programmed Intermittent Epidural Bolus Versus Continuous Epidural Infusion for Third Trimester Medical Termination of Pregnancy Analgesia : a Randomized Study. (PCEA-IMG)
• [2] Clonidine FDA Label
• [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: 516).
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] 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).
• [6] 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.
• [7] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [8] Caco-2 permeability, P-glycoprotein transport ratios and brain penetration of heterocyclic drugs. Int J Pharm. 2003 Sep 16;263(1-2):113-22.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Clonidine-induced gynecomastia and hyperprolactinemia in a 6-year-old child. J Clin Psychiatry. 2005 Dec;66(12):1616-7. doi: 10.4088/jcp.v66n1219f.
• [16] Assessment of MK-912, an alpha 2-adrenoceptor antagonist, with use of intravenous clonidine. Clin Pharmacol Ther. 1989 Jul;46(1):103-9. doi: 10.1038/clpt.1989.113.
• [17] Clonidine effect on insulin secretion and lipolysis in man. Acta Diabetol Lat. 1978 May-Aug;15(3-4):192-7. doi: 10.1007/BF02581064.
• [18] The effects of clonidine hydrochloride versus atenolol monotherapy on serum lipids, lipid subfractions, and apolipoproteins in mild hypertension. Am Heart J. 1990 Jul;120(1):172-9. doi: 10.1016/0002-8703(90)90175-w.
• [19] 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.
• [20] Antihypertensive drugs clonidine, diazoxide, hydralazine and furosemide regulate the production of cytokines by placentas and peripheral blood mononuclear cells in normal pregnancy. J Hypertens. 2006 May;24(5):915-22. doi: 10.1097/01.hjh.0000222762.84605.03.
• [21] Block of neuronal tetrodotoxin-resistant Na+ currents by stereoisomers of piperidine local anesthetics. Anesth Analg. 2000 Dec;91(6):1499-505.
• [22] Clinical profile of levobupivacaine in regional anesthesia: A systematic review. J Anaesthesiol Clin Pharmacol. 2013 Oct;29(4):530-9.
• [23] Pharmacokinetics of levobupivacaine after caudal epidural administration in infants less than 3 months of age. Br J Anaesth. 2005 Oct;95(4):524-9.
• [24] ClinicalTrials.gov (NCT02695654) Effectiveness of Ultrasound Guided Adductor Canal Block on Chronic Pain in Knee Osteoarthritis