Details of the Drug Combination

General Information of Drug Combination (ID: DC6OIUO)

• Drug Combination Name: Clonidine + Gabapentin
• Indication: Shoulder Arthroscopy; Status: Phase 1 [1]
• Component Drugs:
  Clonidine (DM6RZ9Q): Small molecular drug
  Gabapentin (DM6T924): 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	[7]
Membrane copper amine oxidase (AOC3)	TT7HC21	AOC3_HUMAN	Inhibitor	[8]

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	[9]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[10]
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[10]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[10]

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	[11]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[11]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[11]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[11]

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	[12]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases ADR	[12]
G protein-activated inward rectifier potassium channel 1 (KCNJ3)	OTHQG16J	KCNJ3_HUMAN	Increases ADR	[12]
Apoptosis-inducing factor 1, mitochondrial (AIFM1)	OTKPWB7Q	AIFM1_HUMAN	Increases Expression	[13]
Renin (REN)	OT52GZR2	RENI_HUMAN	Decreases Activity	[14]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Increases Expression	[15]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[16]
Somatotropin (GH1)	OT92RTRD	SOMA_HUMAN	Increases Expression	[17]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Decreases Secretion	[18]
Apolipoprotein A-I (APOA1)	OT5THARI	APOA1_HUMAN	Decreases Expression	[19]
Apolipoprotein A-II (APOA2)	OTQ3HGTC	APOA2_HUMAN	Decreases Expression	[19]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[13]
Tumor necrosis factor alpha-induced protein 3 (TNFAIP3)	OTVLI4DD	TNAP3_HUMAN	Increases Expression	[20]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Secretion	[21]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[13]
Caspase-2 (CASP2)	OTUDYSPP	CASP2_HUMAN	Increases Activity	[13]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[13]
Tumor protein D52 (TPD52)	OTPKSK43	TPD52_HUMAN	Increases Expression	[20]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[13]
Programmed cell death protein 4 (PDCD4)	OTZ6NXUX	PDCD4_HUMAN	Decreases Expression	[20]
Bcl2-associated agonist of cell death (BAD)	OT63ERYM	BAD_HUMAN	Increases Expression	[13]
Delta-type opioid receptor (OPRD1)	OT164PA1	OPRD_HUMAN	Increases ADR	[12]
Myeloperoxidase (MPO)	OTOOXLIN	PERM_HUMAN	Increases ADR	[12]
Kappa-type opioid receptor (OPRK1)	OTXCZF4L	OPRK_HUMAN	Increases ADR	[12]

Indication(s) of Gabapentin

Disease Entry	ICD 11	Status	REF
Complex partial seizure	8A68.0	Approved	[5]
Postherpetic neuralgia	1E91.5	Approved	[6]
Solid tumour/cancer	2A00-2F9Z	Phase 3	[5]

Gabapentin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Gamma-aminobutyric acid B receptor (GABBR)	TTDCVZW	GABR1_HUMAN; GABR2_HUMAN	Antagonist	[22]

Gabapentin Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[23]
Organic cation/carnitine transporter 1 (SLC22A4)	DT2EG60	S22A4_HUMAN	Substrate	[24]
L-type amino acid transporter 1 (SLC7A5)	DT48T0N	LAT1_HUMAN	Substrate	[25]

Gabapentin Interacts with 18 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
D(1A) dopamine receptor (DRD1)	OTLZPBT7	DRD1_HUMAN	Increases ADR	[12]
Histamine H1 receptor (HRH1)	OT8F9FV6	HRH1_HUMAN	Increases ADR	[12]
5-hydroxytryptamine receptor 3A (HTR3A)	OTAIV1AK	5HT3A_HUMAN	Increases ADR	[12]
Muscarinic acetylcholine receptor M1 (CHRM1)	OTKW3E6B	ACM1_HUMAN	Increases ADR	[12]
5-hydroxytryptamine receptor 2B (HTR2B)	OTM1AD9J	5HT2B_HUMAN	Increases ADR	[12]
Alpha-1A adrenergic receptor (ADRA1A)	OTUIWCL5	ADA1A_HUMAN	Increases ADR	[12]
5-hydroxytryptamine receptor 2A (HTR2A)	OTWXJX0M	5HT2A_HUMAN	Increases ADR	[12]
Glutamine--fructose-6-phosphate aminotransferase 1 (GFPT1)	OTQBDO45	GFPT1_HUMAN	Increases ADR	[12]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Increases ADR	[12]
Serum paraoxonase/arylesterase 1 (PON1)	OTD0Z2XO	PON1_HUMAN	Decreases Activity	[26]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Activity	[27]
Lactoperoxidase (LPO)	OTJ9QKX9	PERL_HUMAN	Decreases Expression	[28]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Decreases Expression	[28]
Serine/threonine-protein kinase mTOR (MTOR)	OTHH8KU7	MTOR_HUMAN	Decreases Expression	[28]
Glutamate receptor ionotropic, NMDA 1 (GRIN1)	OTZ5YBO8	NMDZ1_HUMAN	Decreases Expression	[28]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[29]
Voltage-dependent calcium channel subunit alpha-2/delta-2 (CACNA2D2)	OTFJXVQQ	CA2D2_HUMAN	Affects Binding	[30]
SH3 and multiple ankyrin repeat domains protein 2 (SHANK2)	OTSQTPFQ	SHAN2_HUMAN	Decreases Expression	[28]

References

• [1] ClinicalTrials.gov (NCT01112878) Oral Clonidine & Gabapentin: Improving Recovery and Pain Management After Outpatient With Major Orthopedic Surgery
• [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: 5483).
• [6] Gabapentin FDA Label
• [7] 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.
• [8] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
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• [10] 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.
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• [12] 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.
• [13] 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.
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• [15] 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.
• [16] 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.
• [17] 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.
• [18] Clonidine effect on insulin secretion and lipolysis in man. Acta Diabetol Lat. 1978 May-Aug;15(3-4):192-7. doi: 10.1007/BF02581064.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Gabapentin increases a tonic inhibitory conductance in hippocampal pyramidal neurons. Anesthesiology. 2006 Aug;105(2):325-33.
• [23] Clinical pharmacokinetic drug interaction studies of gabapentin enacarbil, a novel transported prodrug of gabapentin, with naproxen and cimetidine. Br J Clin Pharmacol. 2010 May;69(5):498-507.
• [24] Effects of genetic variation in the novel organic cation transporter, OCTN1, on the renal clearance of gabapentin. Clin Pharmacol Ther. 2008 Mar;83(3):416-21.
• [25] Transport of gabapentin by LAT1 (SLC7A5). Biochem Pharmacol. 2013 Jun 1;85(11):1672-83.
• [26] Antiepileptic drugs: impacts on human serum paraoxonase-1. J Biochem Mol Toxicol. 2017 Jun;31(6).
• [27] Functional evaluation of polymorphisms in the human ABCB1 gene and the impact on clinical responses of antiepileptic drugs. Pharmacogenet Genomics. 2008 May;18(5):390-402. doi: 10.1097/FPC.0b013e3282f85e36.
• [28] Establishment of a 13 genes-based molecular prediction score model to discriminate the neurotoxic potential of food relevant-chemicals. Toxicol Lett. 2022 Feb 1;355:1-18. doi: 10.1016/j.toxlet.2021.10.013. Epub 2021 Nov 5.
• [29] Effects of the antiepileptic drugs lamotrigine, topiramate and gabapentin on hERG potassium currents. Epilepsy Res. 2005 Jan;63(1):17-25. doi: 10.1016/j.eplepsyres.2004.10.002. Epub 2004 Dec 8.
• [30] Tissue-specific expression and gabapentin-binding properties of calcium channel alpha2delta subunit subtypes. J Membr Biol. 2001 Nov 1;184(1):35-43. doi: 10.1007/s00232-001-0072-7.