Details of the Drug

General Information of Drug (ID: DM93L4X)

• Drug Name: Dexmedetomidine
• Synonyms: Dexmedetomidina; Dexmedetomidinum; MPV 1440; MPV-1440; Precedex (TN); Dexmedetomidine (USAN/INN); (+)-4-((S)-alpha,2,3-Trimethylbenzyl)imidazole; 4-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole; 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

Indication

Disease Entry	ICD 11	Status	REF
Irritability	MB24	Approved	[1], [2]

• Therapeutic Class: Hypnotics and Sedatives
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 200.28
  Topological Polar Surface Area (xlogp); 3.1
  Rotatable Bond Count (rotbonds); 2
  Hydrogen Bond Donor Count (hbonddonor); 1
  Hydrogen Bond Acceptor Count (hbondacc); 1
• ADMET Property:
  Clearance: The drug present in the plasma can be removed from the body at the rate of 11 mL/min/kg [3]
  Half-life: The concentration or amount of drug in body reduced by one-half in 2 hours [3]
  Metabolism: The drug is metabolized via the hepatic [4]
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.089 micromolar/kg/day [5]
  Unbound Fraction: The unbound fraction of drug in plasma is 0.06% [3]
  Vd: The volume of distribution (Vd) of drug is 118 L [6]
• Chemical Identifiers:
  Formula: C13H16N2
  IUPAC Name: 5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole
  Canonical SMILES: CC1=C(C(=CC=C1)[C@H](C)C2=CN=CN2)C
  InChI: InChI=1S/C13H16N2/c1-9-5-4-6-12(10(9)2)11(3)13-7-14-8-15-13/h4-8,11H,1-3H3,(H,14,15)/t11-/m0/s1
  InChIKey: CUHVIMMYOGQXCV-NSHDSACASA-N
• Cross-matching ID:
  PubChem CID: 5311068
  ChEBI ID: CHEBI:4466
  CAS Number: 113775-47-6
  DrugBank ID: DB00633
  TTD ID: D0U3DU
  INTEDE ID: DR0472

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Adrenergic receptor Alpha-2 (ADRA2)	TTQ8AFT	NOUNIPROTAC	Agonist	[7], [8]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Substrate	[9]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Substrate	[10]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Substrate	[11]

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Dexmedetomidine (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Olopatadine	DMKMWQG	Moderate	Additive CNS depression effects by the combination of Dexmedetomidine and Olopatadine.	Conjunctiva disorder [9A60]	[45]
Propofol	DMB4OLE	Moderate	Additive cardiorespiratory depression effects by the combination of Dexmedetomidine and Propofol.	Corneal disease [9A76-9A78]	[46]
Ethanol	DMDRQZU	Moderate	Additive CNS depression effects by the combination of Dexmedetomidine and Ethanol.	Cystitis [GC00]	[45]
Esketamine	DMVU687	Moderate	Additive CNS depression effects by the combination of Dexmedetomidine and Esketamine.	Depression [6A70-6A7Z]	[47]
Allopregnanolone	DMNLHAC	Moderate	Additive CNS depression effects by the combination of Dexmedetomidine and Allopregnanolone.	Mental/behavioural/neurodevelopmental disorder [6E20-6E8Z]	[48]
Lasmiditan	DMXLVDT	Moderate	Additive CNS depression effects by the combination of Dexmedetomidine and Lasmiditan.	Migraine [8A80]	[49]
Flibanserin	DM70DTN	Moderate	Additive CNS depression effects by the combination of Dexmedetomidine and Flibanserin.	Mood disorder [6A60-6E23]	[50]
Thalidomide	DM70BU5	Moderate	Additive CNS depression effects by the combination of Dexmedetomidine and Thalidomide.	Multiple myeloma [2A83]	[51]
Apraclonidine	DMO4PVE	Moderate	Additive CNS depression effects by the combination of Dexmedetomidine and Apraclonidine.	Optic nerve disorder [9C40]	[52]
Dextropropoxyphene	DM23HCX	Major	Additive CNS depression effects by the combination of Dexmedetomidine and Dextropropoxyphene.	Pain [MG30-MG3Z]	[53]
Buprenorphine	DMPRI8G	Major	Additive CNS depression effects by the combination of Dexmedetomidine and Buprenorphine.	Pain [MG30-MG3Z]	[54]

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: 521).
• [2] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [3] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [4] FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. Clin Cancer Res. 2014 Sep 1;20(17):4436-41.
• [5] 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
• [6] An FDA phase I clinical trial of quinacrine sterilization (QS). Int J Gynaecol Obstet. 2003 Oct;83 Suppl 2:S45-9.
• [7] Dexmedetomidine in intensive care unit: a study of hemodynamic changes. Middle East J Anesthesiol. 2002 Oct;16(6):587-95.
• [8] Alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role. Anaesthesia. 1999 Feb;54(2):146-65.
• [9] Metabolic stability and determination of cytochrome P450 isoenzymes' contribution to the metabolism of medetomidine in dog liver microsomes. Biomed Chromatogr. 2010 Aug;24(8):868-77.
• [10] Impact of CYP2A6 gene polymorphism on the pharmacokinetics of dexmedetomidine for premedication. Expert Rev Clin Pharmacol. 2018 Sep;11(9):917-922.
• [11] Predominant role of peripheral catecholamines in the stress-induced modulation of CYP1A2 inducibility by benzo(alpha)pyrene. Basic Clin Pharmacol Toxicol. 2008 Jan;102(1):35-44.
• [12] Roles of cytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, an anticancer prodrug, in human liver microsomes. Drug Metab Dispos. 2000 Dec;28(12):1457-63.
• [13] Effects of polyunsaturated fatty acids on prostaglandin synthesis and cyclooxygenase-mediated DNA adduct formation by heterocyclic aromatic amines in human adenocarcinoma colon cells. Mol Carcinog. 2004 Jul;40(3):180-8.
• [14] Endoxifen and other metabolites of tamoxifen inhibit human hydroxysteroid sulfotransferase 2A1 (hSULT2A1). Drug Metab Dispos. 2014 Nov;42(11):1843-50.
• [15] Cytochrome P450 1A2 (CYP1A2) activity and risk factors for breast cancer: a cross-sectional study. Breast Cancer Res. 2004;6(4):R352-65.
• [16] PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics. 2015 Aug;25(8):416-26.
• [17] The effect of apigenin on pharmacokinetics of imatinib and its metabolite N-desmethyl imatinib in rats. Biomed Res Int. 2013;2013:789184.
• [18] Effects of morin on the pharmacokinetics of etoposide in rats. Biopharm Drug Dispos. 2007 Apr;28(3):151-6.
• [19] The influence of metabolic gene polymorphisms on urinary 1-hydroxypyrene concentrations in Chinese coke oven workers. Sci Total Environ. 2007 Aug 1;381(1-3):38-46.
• [20] Identification of P450 enzymes involved in metabolism of verapamil in humans. Naunyn Schmiedebergs Arch Pharmacol. 1993 Sep;348(3):332-7.
• [21] Metabolism and metabolic inhibition of xanthotoxol in human liver microsomes. Evid Based Complement Alternat Med. 2016;2016:5416509.
• [22] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [23] Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s. Carcinogenesis. 1994 Jan;15(1):5-9.
• [24] Metabolic interactions between acetaminophen (paracetamol) and two flavonoids, luteolin and quercetin, through in-vitro inhibition studies. J Pharm Pharmacol. 2017 Dec;69(12):1762-1772.
• [25] Psychotropic drug interactions with valproate. Clin Neuropharmacol. 2005 Mar-Apr;28(2):96-101.
• [26] The role of human cytochrome P450 enzymes in the formation of 2-hydroxymetronidazole: CYP2A6 is the high affinity (low Km) catalyst. Drug Metab Dispos. 2013 Sep;41(9):1686-94.
• [27] Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth. 1998 Jun;80(6):788-95.
• [28] CYP2A6- and CYP2A13-catalyzed metabolism of the nicotine delta-5'(1')iminium ion. J Pharmacol Exp Ther. 2012 Nov;343(2):307-15.
• [29] Chronic ethanol feeding and folate deficiency activate hepatic endoplasmic reticulum stress pathway in micropigs. Am J Physiol Gastrointest Liver Physiol. 2005 Jul;289(1):G54-63.
• [30] Cytochrome P450 2E1 null mice provide novel protection against cisplatin-induced nephrotoxicity and apoptosis. Kidney Int. 2003 May;63(5):1687-96.
• [31] Acetaminophen induced acute liver failure via oxidative stress and JNK activation: protective role of taurine by the suppression of cytochrome P450 2E1. Free Radic Res. 2010 Mar;44(3):340-55.
• [32] A study on the metabolism of etoposide and possible interactions with antitumor or supporting agents by human liver microsomes. J Pharmacol Exp Ther. 1998 Sep;286(3):1294-300.
• [33] Novel metabolic pathway of estrone and 17beta-estradiol catalyzed by cytochrome P-450. Drug Metab Dispos. 2000 Feb;28(2):110-2.
• [34] Inhibition of cytochrome P450 2E1 by propofol in human and porcine liver microsomes. Biochem Pharmacol. 2002 Oct 1;64(7):1151-6.
• [35] CYP2E1 and clinical features in alcoholics. Neuropsychobiology. 2003;47(2):86-9.
• [36] 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.
• [37] Meperidine, remifentanil and tramadol but not sufentanil interact with alpha(2)-adrenoceptors in alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptor ... Eur J Pharmacol. 2008 Mar 17;582(1-3):70-7.
• [38] Clinical pharmacokinetics of lofexidine, the alpha 2-adrenergic receptor agonist, in opiate addicts plasma using a highly sensitive liquid chromatography tandem mass spectrometric analysis. Am J DrugAlcohol Abuse. 2008;34(5):611-6.
• [39] Emerging drugs for attention-deficit/hyperactivity disorder. Expert Opin Emerg Drugs. 2007 Sep;12(3):423-34.
• [40] Acute neurotoxicity after yohimbine ingestion by a body builder. Clin Toxicol (Phila). 2009 Sep;47(8):827-9.
• [41] Centrally acting sympathetic inhibitors for therapy of patients with hypertension. Nippon Rinsho. 1997 Aug;55(8):2081-5.
• [42] Tizanidine. A review of its pharmacology, clinical efficacy and tolerability in the management of spasticity associated with cerebral and spinal disorders. Drugs. 1997 Mar;53(3):435-52.
• [43] Potent alpha(2A)-adrenoceptor-mediated vasoconstriction by brimonidine in porcine ciliary arteries. Invest Ophthalmol Vis Sci. 2001 Aug;42(9):2049-55.
• [44] Increased alpha2-adrenergic constriction of isolated arterioles in diffuse scleroderma. Arthritis Rheum. 2000 Aug;43(8):1886-90.
• [45] Warrington SJ, Ankier SI, Turner P "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology 15 (1986): 31-7. [PMID: 3725002]
• [46] Gill SS, Wright EM, Reilly CS "Pharmacokinetic interaction of propofol and fentanyl: single bolus injection study." Br J Anaesth 65 (1990): 760-5. [PMID: 2265045]
• [47] Cerner Multum, Inc. "Australian Product Information.".
• [48] Product Information. Zulresso (brexanolone). Sage Therapeutics, Inc., Cambridge, MA.
• [49] Product Information. Reyvow (lasmiditan). Lilly, Eli and Company, Indianapolis, IN.
• [50] Product Information. Addyi (flibanserin). Sprout Pharmaceuticals, Raleigh, NC.
• [51] Product Information. Thalomid (thalidomide). Celgene Corporation, Warren, NJ.
• [52] Product Information. Alphagan (brimonidine ophthalmic). Allergan Inc, Irvine, CA.
• [53] Hansen BS, Dam M, Brandt J, et al "Influence of dextropropoxyphene on steady state serum levels and protein binding of three anti-epileptic drugs in man." Acta Neurol Scand 61 (1980): 357-67. [PMID: 6998251]
• [54] Sekar M, Mimpriss TJ "Buprenorphine, benzodiazepines and prolonged respiratory depression." Anaesthesia 42 (1987): 567-8. [PMID: 3592200]