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Identification
NameRizatriptan
Accession NumberDB00953  (APRD00008)
Typesmall molecule
Groupsapproved
Description

Rizatriptan is a triptan drug used for the treatment of migraine headaches. It is a selective 5-hydroxytryptamine1 receptor subtype agonist.

Structure
Thumb
Synonyms
SynonymLanguageCode
RisatriptanNot AvailableNot Available
Rizatriptan benzoatNot AvailableNot Available
Rizatriptan benzoateNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
MaxaltNot Available
Maxalt MLTNot Available
Maxalt-MLTNot Available
Brand mixturesNot Available
Categories
CAS number145202-66-0
WeightAverage: 269.3449
Monoisotopic: 269.164045633
Chemical FormulaC15H19N5
InChI KeyInChIKey=ULFRLSNUDGIQQP-UHFFFAOYSA-N
InChI
InChI=1S/C15H19N5/c1-19(2)6-5-13-8-17-15-4-3-12(7-14(13)15)9-20-11-16-10-18-20/h3-4,7-8,10-11,17H,5-6,9H2,1-2H3
IUPAC Name
dimethyl({2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethyl})amine
SMILES
CN(C)CCC1=CNC2=C1C=C(CN1C=NC=N1)C=C2
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassIndoles and Derivatives
SubclassTryptamines and Derivatives
Direct parentTryptamines and Derivatives
Alternative parentsIndoles; Benzene and Substituted Derivatives; Substituted Pyrroles; Triazoles; Tertiary Amines; Polyamines
Substituentsindole; benzene; substituted pyrrole; 1,2,4-triazole; azole; pyrrole; tertiary amine; polyamine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the tryptamines and derivatives. These are compounds containing the tryptamine backbone, which is structurally characterized by an indole ring subsituted at the thrid position by an ethanamine.
Pharmacology
IndicationFor treatment of acute migraine attacks with or without aura.
PharmacodynamicsRizatriptan is a selective agonist of serotonin (5-hydroxytryptamine; 5-HT) type 1B and 1D receptors. It is structurally and pharmacologically related to other selective 5-HT1B/1D receptor agonists and has only a weak affinity for 5-HT1A, 5-HT5A, and 5-HT7 receptors and no significant affinity or pharmacological activity at 5-HT2, 5-HT3 or 5-HT4 receptor subtypes or at alpha1-, alpha2-, or beta-adrenergic, dopamine1,; dopamine2; muscarinic, or benzodiazepine receptors. This action in humans correlates with the relief of migraine headache. In addition to causing vasoconstriction, experimental data from animal studies show that Rizatriptan also activates 5-HT1 receptors on peripheral terminals of the trigeminal nerve innervating cranial blood vessels, which may also contribute to the antimigrainous effect of Rizatriptan in humans.
Mechanism of actionThree distinct pharmacological actions have been implicated in the antimigraine effect of the triptans: (1) stimulation of presynaptic 5-HT1D receptors, which serves to inhibit both dural vasodilation and inflammation; (2) direct inhibition of trigeminal nuclei cell excitability via 5-HT1B/1D receptor agonism in the brainstem and (3) vasoconstriction of meningeal, dural, cerebral or pial vessels as a result of vascular 5-HT1B receptor agonism.
AbsorptionRapid following oral administration. Bioavailability is 45%. Food has no effect on the bioavailability of rizatriptan. However, administering rizatriptan with food will delay by 1 hour the time to reach peak plasma concentration. The rate of absorption is not affected by the presence of a migraine attack.
Volume of distribution
  • 140 L [male]
  • 110 L [female]
Protein binding14%
Metabolism

Rizatriptan is metabolized by monoamine oxidase A isoenzyme (MAO-A) to an inactive indole acetic acid metabolite. In addition, several other inactive metabolites are formed. An active metabolite, N-monodesmethyl-rizatriptan, with pharmacological activity similar to that of the parent compound has been identified in small concentrations (14%) in the plasma.

SubstrateEnzymesProduct
Rizatriptan
    N-monodesmethyl-rizatriptanDetails
    Route of eliminationApproximately 14% of an oral dose is excreted in urine as unchanged rizatriptan while 51% is excreted as indole acetic acid metabolite, indicating substantial first pass metabolism.
    Half life2-3 hours
    ClearanceNot Available
    ToxicitySymptoms of overdose include dizziness, fainting, heart and blood vessel problems, high blood pressure, loss of bowel and bladder control, slow heartbeat, and vomiting.
    Affected organisms
    • Humans and other mammals
    PathwaysNot Available
    SNP Mediated Effects
    Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeEffectReference(s)
    Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3
    Gene symbol: GNB3
    UniProt: P16520
    rs5443 Not AvailableT AlleleBetter response to drug treatment17361120
    SNP Mediated Adverse Drug ReactionsNot Available
    ADMET
    Predicted ADMET features
    Property Value Probability
    Human Intestinal Absorption + 1.0
    Blood Brain Barrier + 0.9406
    Caco-2 permeable + 0.5547
    P-glycoprotein substrate Substrate 0.7478
    P-glycoprotein inhibitor I Non-inhibitor 0.8752
    P-glycoprotein inhibitor II Non-inhibitor 0.7244
    Renal organic cation transporter Inhibitor 0.7394
    CYP450 2C9 substrate Non-substrate 0.8572
    CYP450 2D6 substrate Non-substrate 0.6765
    CYP450 3A4 substrate Substrate 0.5574
    CYP450 1A2 substrate Non-inhibitor 0.9149
    CYP450 2C9 substrate Non-inhibitor 0.9063
    CYP450 2D6 substrate Non-inhibitor 0.8913
    CYP450 2C19 substrate Non-inhibitor 0.9515
    CYP450 3A4 substrate Non-inhibitor 0.9688
    CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.956
    Ames test AMES toxic 0.5644
    Carcinogenicity Non-carcinogens 0.9133
    Biodegradation Not ready biodegradable 0.9439
    Rat acute toxicity 2.5433 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Weak inhibitor 0.7051
    hERG inhibition (predictor II) Non-inhibitor 0.7265
    Pharmacoeconomics
    Manufacturers
    • Merck and co inc
    Packagers
    Dosage forms
    FormRouteStrength
    TabletOral
    WaferOral
    Prices
    Unit descriptionCostUnit
    Maxalt 12 10 mg tablet Box333.27USDbox
    Maxalt 12 5 mg tablet Box333.27USDbox
    Maxalt-MLT 3 5 mg Dispersible Tablet Box286.96USDbox
    Maxalt 9 5 mg tablet Box203.46USDbox
    Maxalt 6 5 mg tablet Box107.44USDbox
    Maxalt-MLT 3 10 mg Dispersible Tablet Box83.32USDbox
    Maxalt mlt 10 mg tablet26.7USDtablet
    Maxalt mlt 5 mg tablet26.7USDtablet
    Maxalt 10 mg tablet25.31USDtablet
    Maxalt 5 mg tablet22.98USDtablet
    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
    Patents
    CountryPatent NumberApprovedExpires (estimated)
    United States56021621994-02-112014-02-11
    United States52985201995-06-292012-06-29
    Canada20601391998-12-012012-01-28
    Properties
    Statesolid
    Experimental Properties
    PropertyValueSource
    melting point178-180 °CNot Available
    water solubility42 mg/mL (for free base)Not Available
    logP1.4Not Available
    Predicted Properties
    PropertyValueSource
    water solubility3.38e-01 g/lALOGPS
    logP1.67ALOGPS
    logP1.77ChemAxon
    logS-2.9ALOGPS
    pKa (strongest acidic)17.24ChemAxon
    pKa (strongest basic)9.56ChemAxon
    physiological charge1ChemAxon
    hydrogen acceptor count3ChemAxon
    hydrogen donor count1ChemAxon
    polar surface area49.74ChemAxon
    rotatable bond count5ChemAxon
    refractivity93.13ChemAxon
    polarizability30ChemAxon
    number of rings3ChemAxon
    bioavailability1ChemAxon
    rule of fiveYesChemAxon
    Ghose filterYesChemAxon
    Veber's ruleNoChemAxon
    MDDR-like ruleNoChemAxon
    Spectra
    SpectraNot Available
    References
    Synthesis Reference

    Montserrat Armengol Asparo, Pere Dalmases Barjoan, “Process for preparing a rizatriptan.” U.S. Patent US20050148778, issued July 07, 2005.

    US20050148778
    General Reference
    1. Wellington K, Plosker GL: Rizatriptan: an update of its use in the management of migraine. Drugs. 2002;62(10):1539-74. Pubmed
    2. Wellington K, Jarvis B: Spotlight on rizatriptan in migraine. CNS Drugs. 2002;16(10):715-20. Pubmed
    3. Ikemoto F, Toru T, Aijima H, Natsumeda Y: [Rizatriptan (Maxalt), a new entity of triptan for migraine: pharmacology and therapeutic relevance] Nippon Yakurigaku Zasshi. 2004 Apr;123(4):295-302. Pubmed
    4. Villalon CM, Centurion D, Valdivia LF, De Vries P, Saxena PR: An introduction to migraine: from ancient treatment to functional pharmacology and antimigraine therapy. Proc West Pharmacol Soc. 2002;45:199-210. Pubmed
    5. Tfelt-Hansen P, De Vries P, Saxena PR: Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy. Drugs. 2000 Dec;60(6):1259-87. Pubmed
    External Links
    ResourceLink
    KEGG DrugD00675
    PubChem Compound5078
    PubChem Substance46506557
    ChemSpider4900
    ChEBI48273
    ChEMBLCHEMBL905
    Therapeutic Targets DatabaseDAP000220
    PharmGKBPA451264
    IUPHAR51
    Guide to Pharmacology51
    Drug Product Database2240520
    RxListhttp://www.rxlist.com/cgi/generic2/rizatrip.htm
    Drugs.comhttp://www.drugs.com/cdi/rizatriptan.html
    PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/max1248.shtml
    WikipediaRizatriptan
    ATC CodesN02CC04
    AHFS Codes
    • 28:32.28
    PDB EntriesNot Available
    FDA labelshow(873 KB)
    MSDSshow(57.7 KB)
    Interactions
    Drug Interactions
    Drug
    CitalopramIncreased risk of CNS adverse effects
    DesvenlafaxineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
    DihydroergotaminePossible severe and prolonged vasoconstriction
    ErgotaminePossible severe and prolonged vasoconstriction
    EscitalopramIncreased risk of CNS adverse effects
    FluoxetineIncreased risk of CNS adverse effects
    FluvoxamineIncreased risk of CNS adverse effects
    IsocarboxazidThe MAO inhibitor, isocarboxazid, may decrease the metabolism and clearance of the serotonin 5-HT receptor agonist, rizatriptan. Concomitant therapy is contraindicated.
    MethysergidePossible severe and prolonged vasoconstriction
    MoclobemideThe MAO inhibitor, moclobemide, may decrease the metabolism and clearance of the serotonin 5-HT receptor agonist, rizatriptan. Concomitant therapy is contraindicated.
    NefazodoneIncreased risk of CNS adverse effects
    ParoxetineIncreased risk of CNS adverse effects
    PhenelzineThe MAO inhibitor, phenelzine, may decrease the metabolism and clearance of the serotonin 5-HT receptor agonist, rizatriptan. Concomitant therapy is contraindicated.
    PropranololPropranolol increases the effect and toxicity of rizatriptan
    TramadolIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
    TranylcypromineThe MAO inhibitor, Tranylcypromine, may reduce the metabolism and clearance of the serotonin 5-HT1D receptor agonist, Rizatriptan. Risk of serotonin syndrome and Rizatriptan toxicity. Concomitant therapy should be avoided.
    TrazodoneIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
    TrimipramineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
    VenlafaxineIncreased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
    ZolmitriptanConcomitant use of two serotonin 5-HT1D receptor agonists, such as zolmitriptan and rizatriptan, may result in additive vasoconstrictive effects. Concomitant use within 24 hours is contraindicated.
    Food InteractionsNot Available

    1. 5-hydroxytryptamine receptor 1D

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: agonist

    Components

    Name UniProt ID Details
    5-hydroxytryptamine receptor 1D P28221 Details

    References:

    1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
    2. Longmore J, Hargreaves RJ, Boulanger CM, Brown MJ, Desta B, Ferro A, Schofield WN, Taylor AA, Hill RG: Comparison of the vasoconstrictor properties of the 5-HT1D-receptor agonists rizatriptan (MK-462) and sumatriptan in human isolated coronary artery: outcome of two independent studies using different experimental protocols. Funct Neurol. 1997 Jan-Feb;12(1):3-9. Pubmed
    3. Longmore J, Boulanger CM, Desta B, Hill RG, Schofield WN, Taylor AA: 5-HT1D receptor agonists and human coronary artery reactivity in vitro: crossover comparisons of 5-HT and sumatriptan with rizatriptan and L-741,519. Br J Clin Pharmacol. 1996 Oct;42(4):431-41. Pubmed
    4. Sciberras DG, Polvino WJ, Gertz BJ, Cheng H, Stepanavage M, Wittreich J, Olah T, Edwards M, Mant T: Initial human experience with MK-462 (rizatriptan): a novel 5-HT1D agonist. Br J Clin Pharmacol. 1997 Jan;43(1):49-54. Pubmed
    5. Williamson DJ, Hill RG, Shepheard SL, Hargreaves RJ: The anti-migraine 5-HT agonist rizatriptan inhibits neurogenic dural vasodilation in anaesthetized guinea-pigs. Br J Pharmacol. 2001 Aug;133(7):1029-34. Pubmed
    6. Wackenfors A, Jarvius M, Ingemansson R, Edvinsson L, Malmsjo M: Triptans induce vasoconstriction of human arteries and veins from the thoracic wall. J Cardiovasc Pharmacol. 2005 May;45(5):476-84. Pubmed
    7. Wellington K, Plosker GL: Rizatriptan: an update of its use in the management of migraine. Drugs. 2002;62(10):1539-74. Pubmed
    8. Wellington K, Jarvis B: Spotlight on rizatriptan in migraine. CNS Drugs. 2002;16(10):715-20. Pubmed
    9. Ikemoto F, Toru T, Aijima H, Natsumeda Y: [Rizatriptan (Maxalt), a new entity of triptan for migraine: pharmacology and therapeutic relevance] Nippon Yakurigaku Zasshi. 2004 Apr;123(4):295-302. Pubmed

    2. 5-hydroxytryptamine receptor 1B

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: agonist

    Components

    Name UniProt ID Details
    5-hydroxytryptamine receptor 1B P28222 Details

    References:

    1. Wellington K, Plosker GL: Rizatriptan: an update of its use in the management of migraine. Drugs. 2002;62(10):1539-74. Pubmed
    2. Wellington K, Jarvis B: Spotlight on rizatriptan in migraine. CNS Drugs. 2002;16(10):715-20. Pubmed
    3. Ikemoto F, Toru T, Aijima H, Natsumeda Y: [Rizatriptan (Maxalt), a new entity of triptan for migraine: pharmacology and therapeutic relevance] Nippon Yakurigaku Zasshi. 2004 Apr;123(4):295-302. Pubmed
    4. Pauwels PJ, Palmier C, Dupuis DS, Colpaert FC: Interaction of 5-HT1B/D ligands with recombinant h 5-HT1A receptors: intrinsic activity and modulation by G-protein activation state. Naunyn Schmiedebergs Arch Pharmacol. 1998 May;357(5):490-9. Pubmed
    5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
    6. Williamson DJ, Hill RG, Shepheard SL, Hargreaves RJ: The anti-migraine 5-HT agonist rizatriptan inhibits neurogenic dural vasodilation in anaesthetized guinea-pigs. Br J Pharmacol. 2001 Aug;133(7):1029-34. Pubmed
    7. Wackenfors A, Jarvius M, Ingemansson R, Edvinsson L, Malmsjo M: Triptans induce vasoconstriction of human arteries and veins from the thoracic wall. J Cardiovasc Pharmacol. 2005 May;45(5):476-84. Pubmed

    3. 5-hydroxytryptamine receptor 1F

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: agonist

    Components

    Name UniProt ID Details
    5-hydroxytryptamine receptor 1F P30939 Details

    References:

    1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
    2. Villalon CM, Centurion D, Valdivia LF, de Vries P, Saxena PR: Migraine: pathophysiology, pharmacology, treatment and future trends. Curr Vasc Pharmacol. 2003 Mar;1(1):71-84. Pubmed
    3. Villalon CM, Centurion D, Valdivia LF, De Vries P, Saxena PR: An introduction to migraine: from ancient treatment to functional pharmacology and antimigraine therapy. Proc West Pharmacol Soc. 2002;45:199-210. Pubmed
    4. Wainscott DB, Johnson KW, Phebus LA, Schaus JM, Nelson DL: Human 5-HT1F receptor-stimulated [35S]GTPgammaS binding: correlation with inhibition of guinea pig dural plasma protein extravasation. Eur J Pharmacol. 1998 Jul 3;352(1):117-24. Pubmed
    5. Goadsby PJ, Classey JD: Evidence for serotonin (5-HT)1B, 5-HT1D and 5-HT1F receptor inhibitory effects on trigeminal neurons with craniovascular input. Neuroscience. 2003;122(2):491-8. Pubmed

    1. Amine oxidase [flavin-containing] A

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Amine oxidase [flavin-containing] A P21397 Details

    References:

    1. Iwasa T, Sano H, Sugiura A, Uchiyama N, Hara K, Okochi H, Nakagawa K, Yasumori T, Ishizaki T: An in vitro interethnic comparison of monoamine oxidase activities between Japanese and Caucasian livers using rizatriptan, a serotonin receptor 1B/1D agonist, as a model drug. Br J Clin Pharmacol. 2003 Nov;56(5):537-44. Pubmed
    2. Van Haarst AD, Van Gerven JM, Cohen AF, De Smet M, Sterrett A, Birk KL, Fisher AL, De Puy ME, Goldberg MR, Musson DG: The effects of moclobemide on the pharmacokinetics of the 5-HT1B/1D agonist rizatriptan in healthy volunteers. Br J Clin Pharmacol. 1999 Aug;48(2):190-6. Pubmed

    2. Cytochrome P450 1A2

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Cytochrome P450 1A2 P05177 Details

    References:

    1. Sternieri E, Coccia CP, Pinetti D, Ferrari A: Pharmacokinetics and interactions of headache medications, part I: introduction, pharmacokinetics, metabolism and acute treatments. Expert Opin Drug Metab Toxicol. 2006 Dec;2(6):961-79. Pubmed

    Comments
    Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12