Identification

Name
Cevimeline
Accession Number
DB00185  (APRD00224)
Type
Small Molecule
Groups
Approved
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
Synonyms
  • 2-Methyspiro(1,3-oxathiolane-5,3)quinuclidine
  • Cevimelina
  • Cevimelinum
  • Sni 2011
Product Ingredients
IngredientUNIICASInChI Key
Cevimeline hydrochlorideP81Q6V85NP153504-70-2ZSTLCHCDLIUXJE-ZGBAEQJLSA-N
Product Images
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
CevimelineCapsule30 mg/1OralSun Pharmaceutical Industries Limited2016-03-10Not applicableUs
Cevimeline HydrochlorideCapsule30 mg/1OralAmerincan Health Packaging2015-03-312018-11-30Us63304 0479 01 nlmimage10 4c3da66d
EvoxacCapsule30 mg/1OralStat Rx USA2000-01-11Not applicableUs
EvoxacCapsule30 mg/1OralDaiichi Sankyo, Inc.2000-01-12Not applicableUs
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Cevimeline HydrochlorideCapsule30 mg/1OralAvera McKennan Hospital2015-10-302018-06-07Us69189 039920180907 15195 1vdi59e
Cevimeline HydrochlorideCapsule30 mg/1OralApotex Corporation2012-10-082018-08-14Us60505 3145 01 nlmimage10 f13af8e7
Cevimeline HydrochlorideCapsule30 mg/1OralWest-Ward Pharmaceuticals Corp.2013-07-08Not applicableUs00054 0334 25 nlmimage10 2e45972c
Cevimeline HydrochlorideCapsule30 mg/1OralIngenus Pharmaceuticals Nj, Llc2014-06-17Not applicableUs
Cevimeline HydrochlorideCapsule30 mg/1OralNovel Laboratories, Inc.2016-12-30Not applicableUs
Cevimeline HydrochlorideCapsule30 mg/1OralRising Pharmaceuticals2014-06-17Not applicableUs
International/Other Brands
Saligren
Categories
UNII
K9V0CDQ56E
CAS number
107233-08-9
Weight
Average: 199.313
Monoisotopic: 199.103084861
Chemical Formula
C10H17NOS
InChI Key
WUTYZMFRCNBCHQ-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

Pharmacology

Indication

For the treatment of symptoms of dry mouth in patients with Sjögren's Syndrome.

Associated Conditions
Pharmacodynamics

Cevimeline 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 action

Muscarinic 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.

TargetActionsOrganism
AMuscarinic acetylcholine receptor M3
agonist
Human
AMuscarinic acetylcholine receptor M1
agonist
Human
Absorption

Rapidly 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.

Route of elimination

After 24 hours, 84% of a 30 mg dose of cevimeline was excreted in urine.

Half life

5 ± 1 hours

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Cytochrome P450 2D6CYP2D6*3Not AvailableC alleleEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*4Not AvailableC alleleEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*5Not AvailableWhole-gene deletionEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*6Not Available1707delTEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*7Not Available2935A>CEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*8Not Available1758G>TEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*11Not Available883G>CEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*12Not Available124G>AEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*13Not AvailableCYP2D7/2D6 hybrid gene structureEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*14ANot Available1758G>AEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*15Not Available137insT, 137_138insTEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*19Not Available2539_2542delAACTEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*20Not Available1973_1974insGEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*21Not Available2573insCEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*31Not Available-1770G>A / -1584C>G  … show all Effect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*36Not Available100C>T / -1426C>T  … show all Effect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*38Not Available2587_2590delGACTEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*40Not Available1863_1864ins(TTT CGC CCC)2Effect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*42Not Available3259_3260insGTEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*44Not Available2950G>CEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*47Not Available100C>T / -1426C>T  … show all Effect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*51Not Available-1584C>G / -1235A>G  … show all Effect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*56Not Available3201C>TEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*57Not Available100C>T / 310G>T  … show all Effect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*62Not Available4044C>TEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*68ANot Available-1426C>T / -1235A>G  … show all Effect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*68BNot AvailableSimilar but not identical switch region compared to CYP2D6*68A. Found in tandem arrangement with CYP2D6*4.Effect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*69Not Available2988G>A / -1426C>T  … show all Effect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*92Not Available1995delCEffect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*100Not Available-1426C>T / -1235A>G  … show all Effect InferredPoor metabolizer, more adverse reactions.Details
Cytochrome P450 2D6CYP2D6*101Not Available-1426C>T / -1235A>G  … show all Effect InferredPoor metabolizer, more adverse reactions.Details

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Cevimeline.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Cevimeline.
1,10-PhenanthrolineThe risk or severity of adverse effects can be increased when 1,10-Phenanthroline is combined with Cevimeline.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Cevimeline.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Cevimeline.
4-MethoxyamphetamineThe metabolism of 4-Methoxyamphetamine can be decreased when combined with Cevimeline.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Cevimeline.
6-Deoxyerythronolide BThe metabolism of Cevimeline can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Cevimeline.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Cevimeline.
Food Interactions
Not Available

References

General References
Not Available
External Links
Human Metabolome Database
HMDB0014331
KEGG Drug
D00661
PubChem Compound
25137844
PubChem Substance
46507202
ChemSpider
21864737
ChEBI
3568
Therapeutic Targets Database
DAP000075
PharmGKB
PA164754754
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Cevimeline
ATC Codes
N07AX03 — Cevimeline
FDA label
Download (34.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedTreatmentDry Mouth2
3CompletedSupportive CareHead and Neck Carcinoma / Oral Complications / Radiation Toxicity1
4CompletedTreatmentXerostomia1
Not AvailableCompletedTreatmentDry Mouth1

Pharmacoeconomics

Manufacturers
  • Daiichi sankyo co ltd
Packagers
  • Astellas Pharma Inc.
  • Daiichi Sankyo
Dosage forms
FormRouteStrength
CapsuleOral30 mg/1
Prices
Unit descriptionCostUnit
Evoxac 30 mg capsule2.69USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5340821No1994-08-232013-07-07Us
US4855290No1989-08-082009-08-30Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)201-203 °C (HCl salt)Not Available
water solubilityVery solubleNot Available
logP1.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility2.41 mg/mLALOGPS
logP1.46ALOGPS
logP1ChemAxon
logS-1.9ALOGPS
pKa (Strongest Basic)8.59ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area12.47 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity55.92 m3·mol-1ChemAxon
Polarizability21.89 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9899
Blood Brain Barrier+0.9823
Caco-2 permeable+0.6465
P-glycoprotein substrateSubstrate0.7063
P-glycoprotein inhibitor INon-inhibitor0.6941
P-glycoprotein inhibitor IINon-inhibitor0.9434
Renal organic cation transporterInhibitor0.6934
CYP450 2C9 substrateNon-substrate0.8083
CYP450 2D6 substrateSubstrate0.8918
CYP450 3A4 substrateSubstrate0.5719
CYP450 1A2 substrateNon-inhibitor0.8634
CYP450 2C9 inhibitorNon-inhibitor0.9047
CYP450 2D6 inhibitorNon-inhibitor0.6012
CYP450 2C19 inhibitorNon-inhibitor0.7312
CYP450 3A4 inhibitorNon-inhibitor0.9154
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7686
Ames testNon AMES toxic0.7969
CarcinogenicityNon-carcinogens0.9054
BiodegradationNot ready biodegradable0.9942
Rat acute toxicity2.7785 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6383
hERG inhibition (predictor II)Non-inhibitor0.8469
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as azaspirodecane derivatives. These are organic compounds containing a spirodecane moiety with at least one nitrogen atom.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azaspirodecane derivatives
Sub Class
Not Available
Direct Parent
Azaspirodecane derivatives
Alternative Parents
Quinuclidines / Piperidines / Oxathiolanes / Monothioacetals / Trialkylamines / Oxacyclic compounds / Azacyclic compounds / Organopnictogen compounds / Organooxygen compounds / Hydrocarbon derivatives
Substituents
Azaspirodecane / Quinuclidine / Piperidine / Monothioacetal / Oxathiolane / Tertiary amine / Tertiary aliphatic amine / Oxacycle / Azacycle / Hydrocarbon derivative
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
quinuclidines, oxathiolane (CHEBI:3568)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Receptor activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM3
Uniprot ID
P20309
Uniprot Name
Muscarinic acetylcholine receptor M3
Molecular Weight
66127.445 Da
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:17139284]
  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:17016423]
  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. doi: 10.1152/ajpgi.00359.2007. Epub 2008 May 1. [PubMed:18450949]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
General Function
Phosphatidylinositol phospholipase c activity
Specific Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the...
Gene Name
CHRM1
Uniprot ID
P11229
Uniprot Name
Muscarinic acetylcholine receptor M1
Molecular Weight
51420.375 Da
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:17139284]
  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:17016423]
  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:8624083]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
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:11725960]
  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:12608011]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
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:11725960]
  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:12608011]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Nadp binding
Specific Function
This protein is involved in the oxidative metabolism of a variety of xenobiotics such as drugs and pesticides. Form I catalyzes the N-oxygenation of secondary and tertiary amines.
Gene Name
FMO1
Uniprot ID
Q01740
Uniprot Name
Dimethylaniline monooxygenase [N-oxide-forming] 1
Molecular Weight
60310.285 Da
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:11725960]
  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:12608011]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 08:41