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Identification
Name Modafinil
Accession Number DB00745 (APRD00534)
Type small molecule
Groups approved
Description

Modafinil is a stimulant drug marketed as a ‘wakefulness promoting agent’ and is one of the stimulants used in the treatment of narcolepsy. Narcolepsy is caused by dysfunction of a family of wakefulness-promoting and sleep-suppressing peptides, the orexins, whose neurons are activated by modafinil. The prexin neuron activation is associated with psychoactivation and euphoria. The exact mechanism of action is unclear, although in vitro studies have shown it to inhibit the reuptake of dopamine by binding to the dopamine reuptake pump, and lead to an increase in extracellular dopamine. Modafinil activates glutamatergic circuits while inhibiting GABA.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Modafinil [USAN:INN]
Modafinilo [Spanish]
Modafinilum [Latin]
Moderateafinil
Salts Not Available
Brand names
Name Company
Modiodal
Provigil
Sparlon
Brand mixtures Not Available
Categories
  • Central Nervous System Stimulants
  • Central Nervous System Agents
  • Anorexigenic Agents
  • Stimulants
  • Neuroprotective Agents
CAS number 68693-11-8
Weight Average: 273.35
Monoisotopic: 273.082349419
Chemical Formula C15H15NO2S
InChI Key InChIKey=YFGHCGITMMYXAQ-UHFFFAOYSA-N
InChI
InChI=1S/C15H15NO2S/c16-14(17)11-19(18)15(12-7-3-1-4-8-12)13-9-5-2-6-10-13/h1-10,15H,11H2,(H2,16,17)
Plain Text
IUPAC Name
2-(diphenylmethane)sulfinylacetamide
SMILES
NC(=O)CS(=O)C(C1=CC=CC=C1)C1=CC=CC=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Diphenylmethanes
Substructures
  • Amino Ketones
  • Benzene and Derivatives
  • Carbamates and Derivatives
  • Diphenylmethanes
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Carboxylic Acids and Derivatives
  • Sulfoxides
Pharmacology
Indication To improve wakefulness in patients with excessive daytime sleepiness (EDS) associated with narcolepsy.
Pharmacodynamics Modafinil is a stimulant drug marketed as a 'wakefulness promoting agent' and is one of the stimulants used in the treatment of narcolepsy. Narcolepsy is caused by dysfunction of a family of wakefulness-promoting and sleep-suppressing peptides, the orexins, whose neurons are activated by modafinil. The prexin neuron activation is associated with psychoactivation and euphoria. Modafinil is not indicated for complaints of lack of energy or fatigue; but it appears to be very helpful for some patients. Also, it has been used in the treatment of hypersomnia, a disorder in which patients lack the capacity for meaningful sleep and may require ten or more hours per day. Recent studies have have found that modafinil may help recovering cocaine addicts fight their addiction.
Mechanism of action The exact mechanism of action is unclear, although in vitro studies have shown it to inhibit the reuptake of dopamine by binding to the dopamine reuptake pump, and lead to an increase in extracellular dopamine. Modafinil activates glutamatergic circuits while inhibiting GABA. Modafinil is thought to have less potential for abuse than other stimulants due to the absence of any significant euphoric or pleasurable effects. It is possible that modafinil acts by a synergistic combination of mechanisms including direct inhibition of dopamine reuptake, indirect inhibition of noradrenalin reuptake in the VLPO and orexin activation. Modafinil has partial alpha 1B-adrenergic agonist effects by directly stimulating the receptors.
Absorption Rapid following oral administration.
Volume of distribution
  • 0.9 L/kg
Protein binding 60%
Metabolism Hepatic
Route of elimination The major route of elimination is metabolism (~90%), primarily by the liver, with subsequent renal elimination of the metabolites.
Half life 23-215 hours
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Cephalon inc
  • Cephalon, Inc.
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Provigil 200 mg tablet 15.33 USD tablet
Provigil 100 mg tablet 13.58 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 7297346 2004-05-29 2024-05-29
United States RE37516 1994-10-06 2014-10-06
Canada 2165824 2005-08-02 2014-06-14
Canada 2201967 2002-12-10 2015-10-04
Properties
State solid
Experimental Properties
Property Value Source
melting point 164-166 °C Not Available
water solubility Slightly soluble Not Available
logP 0.6 Not Available
Predicted Properties
Property Value Source
water solubility 6.22e-01 g/l ALOGPS
logP 1.75 ALOGPS
logP 1.53 ChemAxon
logS -2.6 ALOGPS
pKa (strongest acidic) 8.84 ChemAxon
pKa (strongest basic) -4.4 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 2 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 60.16 ChemAxon
rotatable bond count 5 ChemAxon
refractivity 77.39 ChemAxon
polarizability 28.71 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. Lindsay SE, Gudelsky GA, Heaton PC: Use of modafinil for the treatment of attention deficit/hyperactivity disorder. Ann Pharmacother. 2006 Oct;40(10):1829-33. Epub 2006 Sep 5. Pubmed
  2. Ishizuka T, Sakamoto Y, Sakurai T, Yamatodani A: Modafinil increases histamine release in the anterior hypothalamus of rats. Neurosci Lett. 2003 Mar 20;339(2):143-6. Pubmed
External Links
Resource Link
KEGG Drug D01832 Link_out
PubChem Compound 4236 Link_out
PubChem Substance 46504648 Link_out
ChemSpider 4088 Link_out
BindingDB 50156055 Link_out
PharmGKB PA450530 Link_out
Drug Product Database 2239665 Link_out
RxList http://www.rxlist.com/cgi/generic2/modafinil.htm Link_out
Drugs.com http://www.drugs.com/cdi/modafinil.html Link_out
PDRhealth http://www.pdrhealth.com/drugs/rx/rx-mono.aspx?contentFileName=pro1544.html&contentName=Provigil&contentId=631 Link_out
Wikipedia http://en.wikipedia.org/wiki/Modafinil Link_out
ATC Codes
  • N06BA07
AHFS Codes
  • 28:20.92
PDB Entries Not Available
FDA label show (98.9 KB)
MSDS show (57 KB)
Interactions
Drug Interactions
Drug Interaction
Carisoprodol Strong CYP2C19 inhibitors such as modafinil may decrease the metabolism of CYP2C19 substrates such as carisoprodol. Consider an alternative for one of the interacting drugs in order to avoid toxicity of the substrate. Some combinations are specifically contraindicated by manufacturers. Suggested dosage adjustments are also offered by some manufacturers. Please review applicable package inserts. Monitor for increased effects of the CYP substrate if a CYP inhibitor is initiated/dose increased, and decreased effects if a CYP inhibitor is discontinued/dose decreased.
Clozapine Modafinil increases the effect and toxicity of clozapine
Cyclosporine Modafinil decreases the effect of cyclosporine
Ethinyl Estradiol Modafinil may decrease the contraceptive effect of ethinyl estradiol. Hormonal contraception should not be solely relied on during concomitant therapy with modafinil.
Mestranol Modafinil decreases the effect of the contraceptive
Telithromycin Telithromycin may reduce clearance of Modafinil. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Modafinil if Telithromycin is initiated, discontinued or dose changed.
Triazolam Modafinil decreases the effect of triazolam
Trimipramine The strong CYP2C19 inhibitor, Modafinil, may decrease the metabolism and clearance of Trimipramine, a CYP2D6 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimipramine if Modafinil is initiated, discontinued or dose changed.
Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of modafinil by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of modafinil if voriconazole is initiated, discontinued or dose changed.
Food Interactions
  • Take without regard to meals.
Targets

1. Sodium-dependent dopamine transporter

Pharmacological action: yes
Actions: inhibitor

Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals

Organism class: human
UniProt ID: Q01959 Link_out
Gene: SLC6A3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhou J, He R, Johnson KM, Ye Y, Kozikowski AP: Piperidine-based nocaine/modafinil hybrid ligands as highly potent monoamine transporter inhibitors: efficient drug discovery by rational lead hybridization. J Med Chem. 2004 Nov 18;47(24):5821-4. Pubmed
  2. Madras BK, Xie Z, Lin Z, Jassen A, Panas H, Lynch L, Johnson R, Livni E, Spencer TJ, Bonab AA, Miller GM, Fischman AJ: Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. J Pharmacol Exp Ther. 2006 Nov;319(2):561-9. Epub 2006 Aug 2. Pubmed
  3. Swanson JM: Role of executive function in ADHD. J Clin Psychiatry. 2003;64 Suppl 14:35-9. Pubmed
  4. Dopheide MM, Morgan RE, Rodvelt KR, Schachtman TR, Miller DK: Modafinil evokes striatal [(3)H]dopamine release and alters the subjective properties of stimulants. Eur J Pharmacol. 2007 Jul 30;568(1-3):112-23. Epub 2007 Apr 5. Pubmed
  5. Wisor JP, Nishino S, Sora I, Uhl GH, Mignot E, Edgar DM: Dopaminergic role in stimulant-induced wakefulness. J Neurosci. 2001 Mar 1;21(5):1787-94. Pubmed

2. Alpha-1B adrenergic receptor

Pharmacological action: unknown
Actions: partial agonist

This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol- calcium second messenger system

Organism class: human
UniProt ID: P35368 Link_out
Gene: ADRA1B Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Chen CR, Qu WM, Qiu MH, Xu XH, Yao MH, Urade Y, Huang ZL: Modafinil exerts a dose-dependent antiepileptic effect mediated by adrenergic alpha1 and histaminergic H1 receptors in mice. Neuropharmacology. 2007 Sep;53(4):534-41. Epub 2007 Jun 30. Pubmed
Enzymes

1. Cytochrome P450 2C19

Actions: inhibitor, inducer

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 3A4

Actions: substrate, inhibitor, inducer

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 reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Robertson P Jr, Hellriegel ET: Clinical pharmacokinetic profile of modafinil. Clin Pharmacokinet. 2003;42(2):123-37. Pubmed
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 1A2

Actions: inhibitor, inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

4. Cytochrome P450 2B6

Actions: inhibitor, inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20813 Link_out
Gene: CYP2B6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

5. Cytochrome P450 2C9

Actions: inhibitor, inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

6. Cytochrome P450 3A5

Actions: inhibitor, inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20815 Link_out
Gene: CYP3A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19