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Identification
NameCevimeline
Accession NumberDB00185  (APRD00224)
Typesmall molecule
Groupsapproved
Description

Cevimeline is a parasympathomimetic and muscarinic agonist, with particular effect on M3 receptors. It is indicated by the Food and Drug Administration for the treatment of dry mouth associated with Sjögren’s syndrome. [Wikipedia]

Structure
Thumb
SynonymsNot Available
Salts
Name/CAS Structure Properties
Cevimeline hydrochloride
Thumb
  • InChI Key: WUTYZMFRCNBCHQ-PSASIEDQSA-N
  • Monoisotopic Mass: 199.103084861
  • Average Mass: 199.313
DBSALT000805
Brand names
NameCompany
EvoxacNot Available
SaligrenNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number107233-08-9
WeightAverage: 199.313
Monoisotopic: 199.103084861
Chemical FormulaC10H17NOS
InChI KeyWUTYZMFRCNBCHQ-LHIURRSHSA-N
InChI
InChI=1S/C10H17NOS/c1-8-12-10(7-13-8)6-11-4-2-9(10)3-5-11/h8-9H,2-7H2,1H3/t8?,10-/m1/s1
IUPAC Name
(2R)-5'-methyl-4-azaspiro[bicyclo[2.2.2]octane-2,2'-[1,4]oxathiolane]
SMILES
CC1O[C@@]2(CS1)CN1CCC2CC1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassAzaspirodecane Derivatives
SubclassNot Available
Direct parentAzaspirodecane Derivatives
Alternative parentsQuinuclidines; Piperidines; Dithioacetals; Oxathiolanes; Tertiary Amines; Polyamines; Ethers; Thioethers
Substituentsquinuclidine; piperidine; oxathiolane; thioacetal; tertiary amine; ether; polyamine; thioether; amine; organonitrogen compound
Classification descriptionThis compound belongs to the azaspirodecane derivatives. These are organic compounds containing a spirodecane moeity with at least one nitrogen atom.
Pharmacology
IndicationFor the treatment of symptoms of dry mouth in patients with Sjögren's Syndrome.
PharmacodynamicsCevimeline is a cholinergic agonist which binds to muscarinic receptors. Muscarinic agonists in sufficient dosage can increase secretion of exocrine glands, such as salivary and sweat glands and increase tone of the smooth muscle in the gastrointestinal and urinary tracts.
Mechanism of actionMuscarinic agonists such as cevimeline bind and activate the muscarinic M1 and M3 receptors. The M1 receptors are common in secretory glands (exocrine glands such as salivary and sweat glands), and their activation results in an increase in secretion from the secretory glands. The M3 receptors are found on smooth muscles and in many glands which help to stimulate secretion in salivary glands, and their activation generally results in smooth muscle contraction and increased glandular secretions. Therefore, as saliva excretion is increased, the symptoms of dry mouth are relieved.
AbsorptionRapidly absorbed with peak concentration after 1.5 to 2 hours
Volume of distribution
  • 6 L/kg
Protein binding< 20%
Metabolism

Primarily hepatic, isozymes CYP2D6 and CYP3A4 are responsible for the metabolism of cevimeline. Approximately 44.5% of the drug is converted to cis and trans-sulfoxide, 22.3% to glucuronic acid conjugate, and 4% to N-oxide of cevimeline. Approximately 8% of the trans-sulfoxide metabolite is then converted into the corresponding glucuronic acid conjugate.

SubstrateEnzymesProduct
Cevimeline
cevimeline trans-sulfoxideDetails
Cevimeline
cevimeline cis-sulfoxideDetails
Cevimeline
cevimeline cis-sulfoxidationDetails
Cevimeline
cevimeline N-oxideDetails
Cevimeline
Not Available
Glucuronic acidDetails
Route of eliminationAfter 24 hours, 84% of a 30 mg dose of cevimeline was excreted in urine.
Half life5 ± 1 hours
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9899
Blood Brain Barrier + 0.9823
Caco-2 permeable + 0.6465
P-glycoprotein substrate Substrate 0.7063
P-glycoprotein inhibitor I Non-inhibitor 0.6941
P-glycoprotein inhibitor II Non-inhibitor 0.9434
Renal organic cation transporter Inhibitor 0.6934
CYP450 2C9 substrate Non-substrate 0.8083
CYP450 2D6 substrate Substrate 0.8918
CYP450 3A4 substrate Substrate 0.5719
CYP450 1A2 substrate Non-inhibitor 0.8634
CYP450 2C9 substrate Non-inhibitor 0.9047
CYP450 2D6 substrate Non-inhibitor 0.6012
CYP450 2C19 substrate Non-inhibitor 0.7312
CYP450 3A4 substrate Non-inhibitor 0.9154
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7686
Ames test Non AMES toxic 0.7969
Carcinogenicity Non-carcinogens 0.9054
Biodegradation Not ready biodegradable 0.9942
Rat acute toxicity 2.7785 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.6383
hERG inhibition (predictor II) Non-inhibitor 0.8469
Pharmacoeconomics
Manufacturers
  • Daiichi sankyo co ltd
Packagers
Dosage forms
FormRouteStrength
CapsuleOral
Prices
Unit descriptionCostUnit
Evoxac 30 mg capsule2.69USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States53408211993-07-072013-07-07
United States48552901992-08-302009-08-30
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point201-203 °C (HCl salt)Not Available
water solubilityVery solubleNot Available
logP1.3Not Available
Predicted Properties
PropertyValueSource
water solubility2.41e+00 g/lALOGPS
logP1.46ALOGPS
logP1ChemAxon
logS-1.9ALOGPS
pKa (strongest basic)8.59ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count2ChemAxon
hydrogen donor count0ChemAxon
polar surface area12.47ChemAxon
rotatable bond count0ChemAxon
refractivity55.92ChemAxon
polarizability21.89ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00661
ChEBI3568
ChEMBL
Therapeutic Targets DatabaseDAP000075
PharmGKBPA164754754
RxListhttp://www.rxlist.com/cgi/generic/cevimeline.htm
Drugs.comhttp://www.drugs.com/cdi/cevimeline.html
WikipediaCevimeline
ATC CodesN07AX03
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(34.3 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
ConivaptanConivaptan may increase the serum concentration of CYP3A4 substrates such as cevimeline. Upon completion/discontinuation of conivaptan, allow at least 7 days before initiating therapy with drugs that are CYP3A4 substrates.
TacrineThe acetylcholinesterase inhibitor, Tacrine, may increase the adverse/toxic effects of Cevimeline, a cholinergic agonist. Monitor for increased cholinergic effects and toxicity.
Food InteractionsNot Available

Targets

1. Muscarinic acetylcholine receptor M3

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M3 P20309 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Li X, Azlina A, Karabasil MR, Purwanti N, Hasegawa T, Yao C, Akamatsu T, Hosoi K: Degradation of submandibular gland AQP5 by parasympathetic denervation of chorda tympani and its recovery by cevimeline, an M3 muscarinic receptor agonist. Am J Physiol Gastrointest Liver Physiol. 2008 Jul;295(1):G112-G123. Epub 2008 May 1. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Muscarinic acetylcholine receptor M1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Muscarinic acetylcholine receptor M1 P11229 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Fisher A, Heldman E, Gurwitz D, Haring R, Karton Y, Meshulam H, Pittel Z, Marciano D, Brandeis R, Sadot E, Barg Y, Pinkas-Kramarski R, Vogel Z, Ginzburg I, Treves TA, Verchovsky R, Klimowsky S, Korczyn AD: M1 agonists for the treatment of Alzheimer’s disease. Novel properties and clinical update. Ann N Y Acad Sci. 1996 Jan 17;777:189-96. Pubmed

Enzymes

1. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Washio T, Arisawa H, Kohsaka K, Yasuda H: Identification of human drug-metabolizing enzymes involved in the metabolism of SNI-2011. Biol Pharm Bull. 2001 Nov;24(11):1263-6. Pubmed
  2. Washio T, Kohsaka K, Arisawa H, Masunaga H: Pharmacokinetics and metabolism of the novel muscarinic receptor agonist SNI-2011 in rats and dogs. Arzneimittelforschung. 2003;53(1):26-33. Pubmed

2. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Washio T, Arisawa H, Kohsaka K, Yasuda H: Identification of human drug-metabolizing enzymes involved in the metabolism of SNI-2011. Biol Pharm Bull. 2001 Nov;24(11):1263-6. Pubmed
  2. Washio T, Kohsaka K, Arisawa H, Masunaga H: Pharmacokinetics and metabolism of the novel muscarinic receptor agonist SNI-2011 in rats and dogs. Arzneimittelforschung. 2003;53(1):26-33. Pubmed

3. Dimethylaniline monooxygenase [N-oxide-forming] 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Dimethylaniline monooxygenase [N-oxide-forming] 1 Q01740 Details

References:

  1. Washio T, Arisawa H, Kohsaka K, Yasuda H: Identification of human drug-metabolizing enzymes involved in the metabolism of SNI-2011. Biol Pharm Bull. 2001 Nov;24(11):1263-6. Pubmed
  2. Washio T, Kohsaka K, Arisawa H, Masunaga H: Pharmacokinetics and metabolism of the novel muscarinic receptor agonist SNI-2011 in rats and dogs. Arzneimittelforschung. 2003;53(1):26-33. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:08