Pitolisant

Explore a selection of our essential drug information below, or:

Unlock enhanced features & extensive drug insights, including detailed interaction data & regulatory status. Create a free account.

SUBSCRIBERECOMMENDED FOR PHARMA

Explore the full scope of our drug knowledge tailored for pharmaceutical research needs in our data library. Learn more.

Identification

Summary

Pitolisant is an antagonist and inverse agonist at the histamine H3 receptor that is used to treat narcolepsy in adults.

Brand Names

Wakix

Generic Name

Pitolisant

DrugBank Accession Number

DB11642

Background

Pitolisant is a selective antagonist or inverse agonist of the histamine H3 receptor used to treat type 1 or 2 narcolepsy.⁸ Narcolepsy is a chronic neurological disorder that affects 1 in 2,000 individuals and is characterized by excessive daytime sleepiness, abnormal REM sleep manifestations, sleep paralysis and hypnagogic hallucinations.⁴ About 60-70% of patients with narcolepsy experience cataplexy, which is a sudden loss of muscle tone triggered by positive or negative emotions.¹ Histaminergic neuron signalling in the brain plays a role in maintaining wakefulness; by blocking histamine autoreceptors, pitolisant enhances the activity of histaminergic neurons, as well as increasing the signalling of other neurotransmitters in the brain.

In a European clinical trial of adult patients with narcolepsy, there was a reduction in the Epworth Sleepiness Scale (ESS) score from pitolisant therapy compared to placebo.³ The therapeutic effectiveness of pitolisant was comparable to that of modafinil.³ Pitolisant therapy was also effective in treating refractory sleepiness in adolescent patients with narcolepsy, where it decreased ESS score and increased the mean sleep onset latency.² Adolescent patients with cataplexy also experienced a slight improvement in the frequency and severity of symptoms ²; however, the safety of use in adolescent or paediatric patients have not been established with pitolisant. Commonly marketed under the trade name Wakix, oral pitolisant was approved by the EMA in 2016 ⁷ for the treatment of narcolepsy with or without cataplexy. FDA approved the use of pitolisant in 2019 for excessive daytime sleepiness (EDS) associated with narcolepsy in adults.⁸

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 295.85
Monoisotopic: 295.1702922
Chemical Formula: C₁₇H₂₆ClNO

Synonyms

Pitolisant

External IDs

BF-2.649
BF-2649
BF2.649

Unlock the secrets to drugging the undruggable

Discover how groundbreaking research is turning "undruggable" targets into therapeutic opportunities.

Download eBook

Unlock the secrets to drugging the undruggable

Download eBook

Pharmacology

Indication

Pitolisant is indicated for the treatment of excessive daytime sleepiness (EDS) or cataplexy in patients six years of age and older with narcolepsy.^12,13

Reduce drug development failure rates

Build, train, & validate machine-learning models
with evidence-based and structured datasets.

See how

Build, train, & validate predictive machine-learning models with structured datasets.

See how

Associated Conditions

Indication Type	Indication	Approval Level	Age Group	Dose Form
Treatment of	Cataplexy	••••••••••••	•••••	••••••
Treatment of	Excessive daytime sleepiness	••••••••••••		••••••
Treatment of	Narcolepsy with cataplexy	••••••••••••		••••••
Treatment of	Narcolepsy without cataplexy	••••••••••••		••••••

Contraindications & Blackbox Warnings

Prevent Adverse Drug Events Today

Tap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.

Learn more

Avoid life-threatening adverse drug events with our Clinical API

Learn more

Pharmacodynamics

Pitolisant promotes wakefulness in narcolepsy by enhancing histaminergic signalling in the central nervous system. It does not significantly bind to H1, H2, or H4 receptors.⁸ In patients with narcolepsy in presence or absence of cataplexy, treatment of pitolisant was associated with an improvement in the level and duration of wakefulness and daytime alertness assessed by objective measures of ability to sustain wakefulness (e.g. Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) Scores) and attention (e.g. Sustained Attention to Response Task (SART)).[L1471] Pitolisant also improved the frequency and severity of narcolepsy-associated cataplexy.¹ Pitolisant acts as a blocker at hERG channels. In two QT studies, supra-therapeutic doses of pitolisant (3-6-times the therapeutic dose, that is 108 mg to 216 mg) produced mild to moderate prolongation of QTc interval (10-13 ms).[L1471]

Mechanism of action

Signalling of histaminergic neurons plays a key role in activating the arousal system with widespread projections to the whole brain [L1471] via activating orexin receptors.¹ Narcolepsy is characterized by insufficient neurotransmission by orexins, or hypocretins, which are excitatory peptides released by neurons located from the lateral hypothalamus. These neurons project to aminergic neurons, such as histaminergic or noradrenergic neurons, that are responsible for the effects of orexin and control of wakefulness.⁴ Histamine H3 receptors are presynaptic inhibitory autoreceptors ⁶ that are located in the cerebral cortex, hypothalamus, hippocampus, and basal ganglia.⁵ H3 receptors promote the re-uptake of histamine at synaptic terminals and attenuate further histamine release into the synapse.⁴ By blocking H3 autoreceptors and increasing the levels of histamine transmitters at the synapse, pitolisant enhances the activity of histaminergic neurons and promotes wakefulness.[L1471] Inverse agonism of pitolisant at H3 receptors also leads to enhanced synthesis and release of endogenous histamine over the basal level.⁴

Pitolisant acts as a high-affinity competitive antagonist (Ki 0.16 nM) and as an inverse agonist (EC50 1.5 nM) at the human H3 receptor ¹ and mediates its pharmacological action at the presynaptic level.⁵ It is thought to bind to the antagonist binding site of the H3 receptor, which is located within the transmembrane core just below the extracellular loops. Piperidines form a salt bridge with Glu206 in the membrane-spanning segment, and the hydroxyl of Tyr374 is H-bonded with the central oxygen of piperidine.⁴ Pitolisant displays high selectivity for H3 receptors compared to other histamine receptor subtypes. Pitolisant also modulates acetylcholine, noradrenaline and dopamine release in the brain by increasing the levels of neurotransmitters but does not increase dopamine release in the stratal complex, including the nucleus accumbens.[L1471] At lower nanomolar concentrations, pitolisant acts as an inverse agonist at H3 receptors and enhances the release of endogenous histamine over the basal level.⁴

Target	Actions	Organism
AHistamine H3 receptor	antagonist inverse agonist	Humans
NPotassium voltage-gated channel subfamily H member 2	blocker	Humans

Absorption

Pitolisant is rapidly and well absorbed following oral administration, resulting in the drug being 90% absorbed.⁸ In healthy individuals receiving an oral dose of 20 mg, the Cmax was approximately 30 ng/mL.⁴ Following oral administration of pitolisant 35.6 mg once daily, the mean steady state Cmax and AUC were 73 ng/mL and 812 ngxhr/mL, respectively.⁸ The Tmax was typically reached approximately 3 hours following administration.[L1471] Following repeated dosing, the steady-state plasma concentration is achieved after 5-6 days of administration but the inter-individual variability in the time to reach steady-state is reported to be high.[L1471] The absolute bioavailability of pitolisant has not been determined.

Volume of distribution

Following single and multiple oral dosing of pitolisant to healthy male adults at doses between 1 and 240 mg, the apparent volume of distribution (V/F) ranges from 1100 to 2825 L. Pitolisant is thought to be equally distributed between red blood cells and plasma.[L1471] Following intravenous administration of pitolisant in rats and monkeys, the apparent Vd at steady-state was approximately 10-fold greater than total body water. Pitolisant crosses the blood-brain barrier and placenta, and was found in milk in rats.

Protein binding

The serum protein binding of pitolisant is approximately 91% to 96%.⁸ Pitolisant is mainly bound to serum albumin and alpha-1 glycoprotein.¹⁰

Metabolism

Pitolisant is primarily metabolized by CYP2D6 and to a lesser extent by CYP3A4 in the liver. The major non-conjugated metabolites are BP2.941 (piperidine N-oxide) and BP2.951 (5-aminovaleric acid).[L1471] Metabolites can further undergo conjugation with glycine or glucuronic acid, and oxidation to a minimal extent. Most metabolites of pitolisant do not retain considerable pharmacological activities.⁸ Several conjugated metabolites were also identified; the major conjugated inactive metabolite was a glycine conjugate of the acid metabolite of O-dealkylated desaturated pitolisant and a glucuronide of a ketone metabolite of monohydroxy desaturated pitolisant.[L1471]

Due to its extensive metabolism in the liver, the systemic exposure of pitolisant thus adverse events of the drug may be elevated in case of compromised liver function. The dosage adjustments for pitolisant is advised in patients with moderate hepatic impairment.⁸

Hover over products below to view reaction partners

Pitolisant
- BP2.941
- BP2.951

Route of elimination

Following hepatic metabolism, about 63% of total elimination occurs via renal excretion into the urine as an inactive non-conjugated metabolite BP2.951 and a glycine conjugated metabolite.[L1471] About 25% of the total dose administered is excreted through expired air as metabolites, and a small fraction (<3%) of drug can be recovered in faeces.[L1471]

Half-life

Pitolisant has a plasma half-life of 10-12 hours.[L1471] After administration of a single dose of 35.6 mg, the median half-life of pitolisant was approximately 20 hours.⁸

Clearance

The apparent oral clearance (CL/F) of pitolisant was 43.9 L/hr following a single dose of 35.6 mg.⁸ The clearance rate is expected to be lower with increasing age.

Adverse Effects

Improve decision support & research outcomes

With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!

See the data

Improve decision support & research outcomes with our structured adverse effects data.

See a data sample

Toxicity

Symptoms of pitolisant overdose may include headache, insomnia, irritability, nausea and abdominal pain. In case of overdose, hospitalisation and monitoring of the vital functions are recommended. There is no clearly identified antidote.[L1471]

After 1 month in mice, 6 months in rats and 9 months in monkeys, no adverse effect level (NOAEL) were 75, 30 and 12 mg/kg/day, p.o., respectively.[L1471] Pitolisant was not found to be genotoxic in Ames test nor carcinogenic in mouse and rat carcinogenicity studies. In rabbit and rat teratogenicity studies, maternally high toxic doses of pitolisant sperm morphology abnormalities and decreased motility without any significant effect on fertility indexes in male rats. It also decreased the percentage of live conceptuses and increased post-implantation loss in female rats. A delay in post-natal development was observed.[L1471]

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
Integrate drug-drug interactions in your software
1,2-Benzodiazepine	The serum concentration of 1,2-Benzodiazepine can be decreased when it is combined with Pitolisant.
Abacavir	Abacavir may decrease the excretion rate of Pitolisant which could result in a higher serum level.
Abametapir	The serum concentration of Pitolisant can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Pitolisant can be increased when combined with Abatacept.
Abemaciclib	The serum concentration of Abemaciclib can be decreased when it is combined with Pitolisant.

Food Interactions

Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of pitolisant. Dose adjustment may be necessary for co-administration.
Take with or without food. A high-fat meal had no clinically significant effects on drug pharmacokinetics.

Products

Drug product information from 10+ global regions

Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.

Access now

Access drug product information from over 10 global regions.

Access now

Product Ingredients

Ingredient	UNII	CAS	InChI Key
Pitolisant hydrochloride	YV33CH63HI	903576-44-3	XLFKECRRMPOAQS-UHFFFAOYSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Ozawade	Tablet, film coated	17.8 mg	Oral	Bioprojet Pharma	2021-10-25	Not applicable
Ozawade	Tablet, film coated	4.45 mg	Oral	Bioprojet Pharma	2022-06-06	Not applicable
Ozawade	Tablet, film coated	4.45 mg	Oral	Bioprojet Pharma	2021-10-25	Not applicable
Ozawade	Tablet, film coated	17.8 mg	Oral	Bioprojet Pharma	2021-10-25	Not applicable
Wakix	Tablet, film coated	18 mg	Oral	Bioprojet Pharma	2020-12-16	Not applicable

Chemical Identifiers

UNII: 4BC83L4PIY
CAS number: 362665-56-3
InChI Key: NNACHAUCXXVJSP-UHFFFAOYSA-N
InChI: InChI=1S/C17H26ClNO/c18-17-9-7-16(8-10-17)6-4-14-20-15-5-13-19-11-2-1-3-12-19/h7-10H,1-6,11-15H2
IUPAC Name: 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine
SMILES: ClC1=CC=C(CCCOCCCN2CCCCC2)C=C1

References

General References

Calik MW: Update on the treatment of narcolepsy: clinical efficacy of pitolisant. Nat Sci Sleep. 2017 Apr 26;9:127-133. doi: 10.2147/NSS.S103462. eCollection 2017. [Article]
Inocente C, Arnulf I, Bastuji H, Thibault-Stoll A, Raoux A, Reimao R, Lin JS, Franco P: Pitolisant, an inverse agonist of the histamine H3 receptor: an alternative stimulant for narcolepsy-cataplexy in teenagers with refractory sleepiness. Clin Neuropharmacol. 2012 Mar-Apr;35(2):55-60. doi: 10.1097/WNF.0b013e318246879d. [Article]
Dauvilliers Y, Bassetti C, Lammers GJ, Arnulf I, Mayer G, Rodenbeck A, Lehert P, Ding CL, Lecomte JM, Schwartz JC: Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013 Nov;12(11):1068-75. doi: 10.1016/S1474-4422(13)70225-4. Epub 2013 Oct 7. [Article]
Schwartz JC: The histamine H3 receptor: from discovery to clinical trials with pitolisant. Br J Pharmacol. 2011 Jun;163(4):713-21. doi: 10.1111/j.1476-5381.2011.01286.x. [Article]
Romigi A, Vitrani G, Lo Giudice T, Centonze D, Franco V: Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy. Drug Des Devel Ther. 2018 Aug 30;12:2665-2675. doi: 10.2147/DDDT.S101145. eCollection 2018. [Article]
Kotanska M, Kuder KJ, Szczepanska K, Sapa J, Kiec-Kononowicz K: The histamine H3 receptor inverse agonist pitolisant reduces body weight in obese mice. Naunyn Schmiedebergs Arch Pharmacol. 2018 Aug;391(8):875-881. doi: 10.1007/s00210-018-1516-2. Epub 2018 May 25. [Article]
Ligneau X, Shah RR, Berrebi-Bertrand I, Mirams GR, Robert P, Landais L, Maison-Blanche P, Faivre JF, Lecomte JM, Schwartz JC: Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro-arrhythmia Assay initiative studies. Br J Pharmacol. 2017 Dec;174(23):4449-4463. doi: 10.1111/bph.14047. Epub 2017 Oct 19. [Article]
FDA Approved Drug Products: WAKIX (pitolisant) tablets, for oral use (August 2019) [Link]
Harmony Biosciences: Wakix (pitolisant) Safety data sheet [Link]
FDA Center for Drug Evaluation and Research: Pitolisant Non-clinical Review(s) [Link]
FDA Approved Drug Products: WAKIX (pitolisant) tablets for oral use (December 2022) [Link]
EMA Approved Drug Products: Wakix (pitolisant) Oral Tablets [Link]
FDA Approved Drug Products: WAKIX (pitolisant) tablets, for oral use (June 2024) [Link]

External Links

Human Metabolome Database: HMDB0256619
ChemSpider: 8123714
BindingDB: 50247053
RxNav: 2197878
ChEBI: 134709
ChEMBL: CHEMBL462605
ZINC: ZINC000034045468
Wikipedia: Pitolisant

Clinical Trials

Clinical Trials Clinical Trial & Rare Diseases Add-on Data Package Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package

Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
Unlock 175K+ rows when you subscribe.View sample data
4	Recruiting	Treatment	Restless Legs Syndrome (RLS)	1	somestatus	stop reason	just information to hide
3	Active Not Recruiting	Treatment	Excessive Daytime Sleepiness / Idiopathic Hypersomnia	1	somestatus	stop reason	just information to hide
3	Active Not Recruiting	Treatment	Narcolepsy With Cataplexy / Narcolepsy Without Cataplexy	1	somestatus	stop reason	just information to hide
3	Completed	Treatment	Cataplexy / Excessive Daytime Sleepiness / Narcolepsy	1	somestatus	stop reason	just information to hide
3	Completed	Treatment	Cataplexy / Excessive Daytime Sleepiness / Narcolepsy / Sleep disorders and disturbances	1	somestatus	stop reason	just information to hide

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, film coated	Oral	17.8 mg
Tablet, film coated	Oral	4.45 mg
Tablet	Oral	20 mg
Tablet	Oral	5 mg
Tablet, film coated	Oral	17.8 mg/1
Tablet, film coated	Oral	18 MG
Tablet, film coated	Oral	4.45 mg/1
Tablet, film coated	Oral	4.5 MG

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US8354430	No	2013-01-15	2026-02-26
US7910605	No	2011-03-22	2022-09-23
US8486947	No	2013-07-16	2029-09-26
US7169928	No	2007-01-30	2020-02-02
US8207197	No	2012-06-26	2029-02-25

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.00142 mg/mL	ALOGPS
logP	4.47	ALOGPS
logP	4.12	Chemaxon
logS	-5.3	ALOGPS
pKa (Strongest Basic)	9.67	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	2	Chemaxon
Hydrogen Donor Count	0	Chemaxon
Polar Surface Area	12.47 Å²	Chemaxon
Rotatable Bond Count	8	Chemaxon
Refractivity	86.81 m³·mol^-1	Chemaxon
Polarizability	35.5 Å³	Chemaxon
Number of Rings	2	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	Yes	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted GC-MS Spectrum - GC-MS	Predicted GC-MS	splash10-0002-9700000000-3dbad73168be1a49e119
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0002-0090000000-21c46c201b0c522cf919
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0006-0290000000-023ea4be96ea22028078
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0002-4980000000-77257c15dc374c28829b
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-000x-8490000000-efee8321e3a106ea64dd
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-002b-7910000000-3cdbc8365a7545ccb153
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-001i-9110000000-33c65c057cb410eeb174
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å²)	Source type	Source
[M-H]-	167.67398	predicted	DeepCCS 1.0 (2019)
[M+H]+	170.03197	predicted	DeepCCS 1.0 (2019)
[M+Na]+	176.35704	predicted	DeepCCS 1.0 (2019)

Targets

Build, predict & validate machine-learning models

Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.

Learn more

Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.

Learn more

Details1. Histamine H3 receptor

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Antagonist
Inverse agonist
Curator comments: Pitolisant acts as a high-affinity competitive antagonist (Ki 0.16 nM) and as an inverse agonist (EC50 1.5 nM) at the human histamine H3 receptor subtype.

General Function: The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system. Signals through the inhibition of adenylate cyclase and displays high constitutive activity (spontaneous activity in the absence of agonist). Agonist stimulation of isoform 3 neither modified adenylate cyclase activity nor induced intracellular calcium mobilization
Specific Function: G protein-coupled acetylcholine receptor activity
Gene Name: HRH3
Uniprot ID: Q9Y5N1
Uniprot Name: Histamine H3 receptor
Molecular Weight: 48670.81 Da

References

Schwartz JC: The histamine H3 receptor: from discovery to clinical trials with pitolisant. Br J Pharmacol. 2011 Jun;163(4):713-21. doi: 10.1111/j.1476-5381.2011.01286.x. [Article]
Khanfar MA, Affini A, Lutsenko K, Nikolic K, Butini S, Stark H: Multiple Targeting Approaches on Histamine H3 Receptor Antagonists. Front Neurosci. 2016 May 30;10:201. doi: 10.3389/fnins.2016.00201. eCollection 2016. [Article]
Inocente C, Arnulf I, Bastuji H, Thibault-Stoll A, Raoux A, Reimao R, Lin JS, Franco P: Pitolisant, an inverse agonist of the histamine H3 receptor: an alternative stimulant for narcolepsy-cataplexy in teenagers with refractory sleepiness. Clin Neuropharmacol. 2012 Mar-Apr;35(2):55-60. doi: 10.1097/WNF.0b013e318246879d. [Article]

Details2. Potassium voltage-gated channel subfamily H member 2

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Blocker

General Function: Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr) (PubMed:18559421, PubMed:26363003, PubMed:27916661)
Specific Function: C3hc4-type ring finger domain binding
Gene Name: KCNH2
Uniprot ID: Q12809
Uniprot Name: Potassium voltage-gated channel subfamily H member 2
Molecular Weight: 126653.52 Da

References

Ligneau X, Shah RR, Berrebi-Bertrand I, Mirams GR, Robert P, Landais L, Maison-Blanche P, Faivre JF, Lecomte JM, Schwartz JC: Nonclinical cardiovascular safety of pitolisant: comparing International Conference on Harmonization S7B and Comprehensive in vitro Pro-arrhythmia Assay initiative studies. Br J Pharmacol. 2017 Dec;174(23):4449-4463. doi: 10.1111/bph.14047. Epub 2017 Oct 19. [Article]

Enzymes

Details1. Cytochrome P450 2D6

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Inhibitor
Curator comments: Pitolisant is an inhibitor of CYP2D6 with moderate potency (IC50 = 2.6 μM).

General Function: A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants
Specific Function: Anandamide 11,12 epoxidase activity
Gene Name: CYP2D6
Uniprot ID: P10635
Uniprot Name: Cytochrome P450 2D6
Molecular Weight: 55768.94 Da

Details2. Cytochrome P450 1A2

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inducer
Curator comments: Inhibition of CYP1A2 by pitolisant was observed in vitro.

General Function: A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable)
Specific Function: Aromatase activity
Gene Name: CYP1A2
Uniprot ID: P05177
Uniprot Name: Cytochrome P450 1A2
Molecular Weight: 58406.915 Da

References

Pitilosant FDA label [File]

Details3. Cytochrome P450 2B6

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inducer
Curator comments: Inhibition of CYP2B6 by pitolisant was observed in vitro.

General Function: A cytochrome P450 monooxygenase involved in the metabolism of endocannabinoids and steroids (PubMed:12865317, PubMed:21289075). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the epoxidation of double bonds of arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:21289075). Hydroxylates steroid hormones, including testosterone at C-16 and estrogens at C-2 (PubMed:12865317, PubMed:21289075). Plays a role in the oxidative metabolism of xenobiotics, including plant lipids and drugs (PubMed:11695850, PubMed:22909231). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850)
Specific Function: Anandamide 11,12 epoxidase activity
Gene Name: CYP2B6
Uniprot ID: P20813
Uniprot Name: Cytochrome P450 2B6
Molecular Weight: 56277.81 Da

References

Pitolisant EMA Label [File]

Details4. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Inducer
Curator comments: Induction of CYP3A4 by pitolisant was observed in vitro.

General Function: A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function: 1,8-cineole 2-exo-monooxygenase activity
Gene Name: CYP3A4
Uniprot ID: P08684
Uniprot Name: Cytochrome P450 3A4
Molecular Weight: 57342.67 Da

Carriers

Details1. Albumin

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Binder

General Function: Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
Specific Function: Antioxidant activity
Gene Name: ALB
Uniprot ID: P02768
Uniprot Name: Albumin
Molecular Weight: 69365.94 Da

References

FDA Center for Drug Evaluation and Research: Pitolisant Non-clinical Review(s) [Link]

Details2. Alpha-1-acid glycoprotein 1

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Binder

General Function: Functions as a transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction
Specific Function: Not Available
Gene Name: ORM1
Uniprot ID: P02763
Uniprot Name: Alpha-1-acid glycoprotein 1
Molecular Weight: 23539.43 Da

References

FDA Center for Drug Evaluation and Research: Pitolisant Non-clinical Review(s) [Link]

Transporters

Details1. Solute carrier family 22 member 1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor
Curator comments: Pitolisant shows greater than 50% inhibition towards OCT1 (organic cation transporters 1) at 1.33 μM, and the extrapolated IC50 of pitolisant is 0.795 μM.

General Function: Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics (PubMed:11388889, PubMed:11408531, PubMed:12439218, PubMed:12719534, PubMed:15389554, PubMed:16263091, PubMed:16272756, PubMed:16581093, PubMed:19536068, PubMed:21128598, PubMed:23680637, PubMed:24961373, PubMed:34040533, PubMed:9187257, PubMed:9260930, PubMed:9655880). Functions as a pH- and Na(+)-independent, bidirectional transporter (By similarity). Cation cellular uptake or release is driven by the electrochemical potential (i.e. membrane potential and concentration gradient) and substrate selectivity (By similarity). Hydrophobicity is a major requirement for recognition in polyvalent substrates and inhibitors (By similarity). Primarily expressed at the basolateral membrane of hepatocytes and proximal tubules and involved in the uptake and disposition of cationic compounds by hepatic and renal clearance from the blood flow (By similarity). Most likely functions as an uptake carrier in enterocytes contributing to the intestinal elimination of organic cations from the systemic circulation (PubMed:16263091). Transports endogenous monoamines such as N-1-methylnicotinamide (NMN), guanidine, histamine, neurotransmitters dopamine, serotonin and adrenaline (PubMed:12439218, PubMed:24961373, PubMed:35469921, PubMed:9260930). Also transports natural polyamines such as spermidine, agmatine and putrescine at low affinity, but relatively high turnover (PubMed:21128598). Involved in the hepatic uptake of vitamin B1/thiamine, hence regulating hepatic lipid and energy metabolism (PubMed:24961373). Mediates the bidirectional transport of acetylcholine (ACh) at the apical membrane of ciliated cell in airway epithelium, thereby playing a role in luminal release of ACh from bronchial epithelium (PubMed:15817714). Transports dopaminergic neuromodulators cyclo(his-pro) and salsolinol with lower efficency (PubMed:17460754). Also capable of transporting non-amine endogenous compounds such as prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) (PubMed:11907186). May contribute to the transport of cationic compounds in testes across the blood-testis-barrier (Probable). Also involved in the uptake of xenobiotics tributylmethylammonium (TBuMA), quinidine, N-methyl-quinine (NMQ), N-methyl-quinidine (NMQD) N-(4,4-azo-n-pentyl)-quinuclidine (APQ), azidoprocainamide methoiodide (AMP), N-(4,4-azo-n-pentyl)-21-deoxyajmalinium (APDA) and 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP) (PubMed:11408531, PubMed:15389554, PubMed:35469921, PubMed:9260930)
Specific Function: (r)-carnitine transmembrane transporter activity
Gene Name: SLC22A1
Uniprot ID: O15245
Uniprot Name: Solute carrier family 22 member 1
Molecular Weight: 61153.345 Da

References

Romigi A, Vitrani G, Lo Giudice T, Centonze D, Franco V: Profile of pitolisant in the management of narcolepsy: design, development, and place in therapy. Drug Des Devel Ther. 2018 Aug 30;12:2665-2675. doi: 10.2147/DDDT.S101145. eCollection 2018. [Article]
Wakix EPAR (EMA) [File]

Drug created at October 17, 2016 21:30 / Updated at July 23, 2024 18:02

Pitolisant

Identification

Structure for Pitolisant (DB11642)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Clinical Trial & Rare Diseases Add-on Data Package

Pharmacoeconomics

Properties

Spectra

Collision Cross Sections (CCS)

Targets

References

References

Enzymes

References

References

Carriers

References

References

Transporters

References