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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 KeyULFRLSNUDGIQQP-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
Not Available
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

Targets

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

Enzymes

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

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