Details of the Drug

General Information of Drug (ID: DM3FXMA)

• Drug Name: Naloxone
• Synonyms: Nalone; Nalossone; Naloxona; Naloxonum; Narcan; Narcanti; Narcon; DBL Naloxone; Nalossone [DCIT]; Naloxone HCl; EN 1530base; DBL Naloxone (TN); L-Naloxone; N-Allylnoroxymorphone; Nalone (TN); Naloxona [INN-Spanish]; Naloxone (INN); Naloxone [INN:BAN]; Naloxonum [INN-Latin]; Narcan (TN); Narcanti (TN); N-Allyl-noroxymorphone; L-N-Allyl-14-hydroxynordihydromorphinone; L-N-Allyl-7,8-dihydro-14-hydroxynormorphinone; N-Allyl-4,5alpha-epoxy-3,14-dihydroxy-6-morphinanon; Morphinan-6-one, 17-allyl-4,5alpha-epoxy-3,14-dihydroxy-(8CI); Morphinan-6-one, 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)-, (5alpha)-(9CI); (-)-N-allyl-14-hydroxynordihydroxymorphinan-6-one; (-)-Naloxone; (5alpha)-3,14-dihydroxy-17-prop-2-en-1-yl-4,5-epoxymorphinan-6-one; (5alpha)-4,5-Epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one; 1-N-Allyl-14-hydroxynordihydromorphinone; 1-N-Allyl-7,8-dihydro-14-hydroxynormorphinone; 12-Allyl-7,7a,8,9-tetrahydro-3,7a-dihydroxy-4aH-8,9c-iminoethanophenanthro(4,5-bcd)furanone; 12-Allyl-7,7a,8,9-tetrahydro-3,7a-dihydroxy-4aH-8,9c-iminoethanophenanthro[4,5-bcd]furan-5(6H)-one; 17-Allyl-4,5-alpha-epoxy-3,14-dihydroxymorphinan-6-one; 17-Allyl-4,5alpha-epoxy-3,14-dihydroxymorphinan-6-one; 17-allyl-3,14-dihydroxy-4,5alpha-epoxymorphinan-6-one; 3,14-dihydroxy-17-(prop-2-en-1-yl)-4,5alpha-epoxymorphinan-6-one

Indication

Disease Entry	ICD 11	Status	REF
Narcotic depression	6A7Z	Approved	[1]
Pain	MG30-MG3Z	Approved	[2]
Pruritus	EC90	Phase 3	[3]
Respiratory depression	MD11.5	Phase 3	[4]
Opioid dependence	6C43.2Z	Phase 1	[4]

• Therapeutic Class: Antinarcotic Agents
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 327.4
  Logarithm of the Partition Coefficient (xlogp); 2.1
  Rotatable Bond Count (rotbonds); 2
  Hydrogen Bond Donor Count (hbonddonor); 2
  Hydrogen Bond Acceptor Count (hbondacc); 5
• ADMET Property:
  Absorption AUC: The area under the plot of plasma concentration (AUC) of drug is 16.7-19.0 mcgh/L [5]
  Absorption Cmax: The maximum plasma concentration (Cmax) of drug is 12.3-12.8 mcg/L [5]
  Absorption Tmax: The time to maximum plasma concentration (Tmax) is 0.25 h [5]
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 1: high solubility and high permeability [6]
  Bioavailability: The bioavailability of drug is 42-47% [5]
  Clearance: The clearance of drug is 2500 L/day [7]
  Elimination: After oral or intravenous administration, naloxone is 25-40% eliminated in the urine within 6 hours, 50% in 24 hours, and 60-70% in 72 hours [5]
  Half-life: The concentration or amount of drug in body reduced by one-half in 1.8 - 2.7 hours [8]
  Metabolism: The drug is metabolized via the glucuronidation to form naloxone-3-glucuronide [5]
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.30545 micromolar/kg/day [9]
  Unbound Fraction: The unbound fraction of drug in plasma is 0.54% [10]
  Vd: The volume of distribution (Vd) of drug is 200 L [7]
• Chemical Identifiers:
  Formula: C19H21NO4
  IUPAC Name: (4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-prop-2-enyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one
  Canonical SMILES: C=CCN1CC[C@]23[C@@H]4C(=O)CC[C@]2([C@H]1CC5=C3C(=C(C=C5)O)O4)O
  InChI: InChI=1S/C19H21NO4/c1-2-8-20-9-7-18-15-11-3-4-12(21)16(15)24-17(18)13(22)5-6-19(18,23)14(20)10-11/h2-4,14,17,21,23H,1,5-10H2/t14-,17+,18+,19-/m1/s1
  InChIKey: UZHSEJADLWPNLE-GRGSLBFTSA-N
• Cross-matching ID:
  PubChem CID: 5284596
  ChEBI ID: CHEBI:7459
  CAS Number: 465-65-6
  DrugBank ID: DB01183
  TTD ID: D0X3FX
  VARIDT ID: DR00698
• Repurposed Drugs (RPD): Click to Jump to the Detailed RPD Information of This Drug

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Opioid receptor mu (MOP)	TTKWM86	OPRM_HUMAN	Antagonist	[11]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Gene/Protein Processing	[12]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Protein Interaction/Cellular Processes	[13]
Interleukin-2 (IL2)	OTGI4NSA	IL2_HUMAN	Protein Interaction/Cellular Processes	[14]
Liver carboxylesterase 1 (CES1)	OT9L0LR8	EST1_HUMAN	Protein Interaction/Cellular Processes	[15]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Gene/Protein Processing	[16]
Natriuretic peptides A (NPPA)	OTMQNTNX	ANF_HUMAN	Gene/Protein Processing	[17]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Gene/Protein Processing	[18]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Gene/Protein Processing	[19]
Renin (REN)	OT52GZR2	RENI_HUMAN	Gene/Protein Processing	[20]
UDP-glucuronosyltransferase 2B7	OT2Q71VQ	UD2B7_HUMAN	Biotransformations	[21]

Molecular Expression Atlas of This Drug

• The Studied Disease: Narcotic depression
• ICD Disease Classification: 6A7Z

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Opioid receptor mu (MOP)	DTT	OPRM1	5.94E-01	-0.02	-0.17

References

• [1] 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: 1668).
• [2] Naloxone FDA Label
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] FDA Approved Drug Products: Kloxxado (Naloxone) Nasal Spray
• [6] BDDCS applied to over 900 drugs
• [7] Rzasa Lynn R, Galinkin JL: Naloxone dosage for opioid reversal: current evidence and clinical implications. Ther Adv Drug Saf. 2018 Jan;9(1):63-88. doi: 10.1177/2042098617744161. Epub 2017 Dec 13.
• [8] Caymen Chemical: Naloxone MSDS
• [9] Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
• [10] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [11] OxyContin abuse and overdose. Postgrad Med. 2009 Mar;121(2):163-7.
• [12] Chronic oxycodone induces integrated stress response in rat brain. BMC Neurosci. 2015 Sep 16;16:58. doi: 10.1186/s12868-015-0197-8.
• [13] Central opioid inhibition of neuroendocrine stress responses in pregnancy in the rat is induced by the neurosteroid allopregnanolone. J Neurosci. 2009 May 20;29(20):6449-60. doi: 10.1523/JNEUROSCI.0708-09.2009.
• [14] Interleukin-2-induced antinociception in morphine-insensitive rats. Acta Pharmacol Sin. 2002 Nov;23(11):981-4.
• [15] Human carboxylesterase 1: from drug metabolism to drug discovery. Biochem Soc Trans. 2003 Jun;31(Pt 3):620-4. doi: 10.1042/bst0310620.
• [16] Differences in the opioid control of luteinizing hormone secretion between pathological and iatrogenic hyperprolactinemic states. J Clin Endocrinol Metab. 1987 Mar;64(3):508-12. doi: 10.1210/jcem-64-3-508.
• [17] Opioid peptides attenuate blood pressure increase in acute respiratory failure. Peptides. 2001 Apr;22(4):631-7. doi: 10.1016/s0196-9781(01)00373-4.
• [18] Endogenous opioids modulate the cardiovascular response to mental stress. Psychoneuroendocrinology. 1990;15(3):185-92. doi: 10.1016/0306-4530(90)90029-9.
• [19] Influence of naloxone on muscle sympathetic nerve activity, systemic and calf haemodynamics and ambulatory blood pressure after exercise in mild essential hypertension. J Hypertens. 1995 Apr;13(4):447-61.
• [20] beta-Endorphin and essential hypertension: importance of the clonidine-naloxone interaction. Acta Physiol Hung. 1985;65(2):217-26.
• [21] Customised in vitro model to detect human metabolism-dependent idiosyncratic drug-induced liver injury. Arch Toxicol. 2018 Jan;92(1):383-399. doi: 10.1007/s00204-017-2036-4. Epub 2017 Jul 31.