Riluzole

Absorption

Riluzole is well-absorbed (approximately 90%), with average absolute oral bioavailability of about 60% (CV=30%). A high fat meal decreases absorption, reducing AUC by about 20% and peak blood levels by about 45%.

Description

Rilutek was launched in Germany, the UK and US (orphan drug status) for treatment of amyotrophic lateral sclerosis (ALS) and is the first drug approved for this indication. A one step synthesis from 4-(trifluoromethoxy)aniline provides a supply of the compound. The source of its neuroprotective and anticonvulsant activity is not clearly understood. It antagonizes excitatory amino acids and blocks presynaptic release of glutamate, is an antagonist of NMDA-induced acetylcholine release and inhibited glutamate and quisqualate induced increases in cGMP but does not bind to NMDA or Kainic receptors. Rilutek has no affinity for glutamate, GABAbenzodiazepine, glycine and adenosine receptors. It easily crosses the blood brain barrier and depresses glutamatergic neurotransmission, stabilizes voltagedependent Na channels in their inactive form and activates G-protein dependent processes.

Chemical properties

White Crystalline Solid

Originator

Rhone-Poulenc Rorer (France)

The Uses of Riluzole

Labeled Riluzole, intended for use as an internal standard for the quantification of Riluzole by GC- or LC-mass spectrometry.

The Uses of Riluzole

A neuroprotective agent. A glutamate release inhibitor. An anticonvulsant

The Uses of Riluzole

A neuroprotective agent. Modulates glutamatergic transmission. A glutamate release inhibitor. An anticonvulsant.

The Uses of Riluzole

anticonvulsant, glutamate release inhibitor, anti-ALS

What are the applications of Application

Riluzole is a sodium channel protein inhibitor

Background

A glutamate antagonist (receptors, glutamate) used as an anticonvulsant (anticonvulsants) and to prolong the survival of patients with amyotrophic lateral sclerosis. Riluzole is marketed as Rilutek by Sanofi.

Indications

For the treatment of amyotrophic lateral sclerosis (ALS, Lou Gehrig's Disease)

Definition

ChEBI: Riluzole is a member of benzothiazoles.

brand name

Rilutek (Sanofi Aventis).

Biological Activity

Novel psychotropic agent with anticonvulsant, hypnotic, anxiolytic, anti-ischemic and anesthetic properties. Riluzole is able to act as a glutamate release inhibitor, blocks voltage-dependent Na + channels and inhibits GABA uptake by striatal synaptosomes.

Biochem/physiol Actions

Glutamate release inhibitor; anticonvulsant

Pharmacokinetics

Riluzole, a member of the benzothiazole class, is indicated for the treatment of patients with amyotrophic lateral sclerosis (ALS). Riluzole extends survival and/or time to tracheostomy. It is also neuroprotective in various in vivo experimental models of neuronal injury involving excitotoxic mechanisms. The etiology and pathogenesis of amyotrophic lateral sclerosis (ALS) are not known, although a number of hypotheses have been advanced. One hypothesis is that motor neurons, made vulnerable through either genetic predisposition or environmental factors, are injured by glutamate. In some cases of familial ALS the enzyme superoxide dismutase has been found to be defective.

Metabolism

Riluzole is extensively metabolized to six major and a number of minor metabolites, which have not all been identified to date. Metabolism is mostly hepatic, consisting of cytochrome P450–dependent hydroxylation and glucuronidation. CYP1A2 is the primary isozyme involved in N-hydroxylation; CYP2D6, CYP2C19, CYP3A4, and CYP2E1 are considered unlikely to contribute significantly to riluzole metabolism in humans.

storage

Room temperature

References

1) Bellingham (2011), A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade; CNS Neurosci. Ther. 17 4 2) Urbani and Belluzzi (2000), Riluzole inhibits the persistent sodium current in mammalian CNS neurons; Eur. J. Neurosci. 12 3567 3) Frizzo et al. (2004), Riluzole enhances glutamate uptake in rat astrocyte cultures; Cell Mol. Neurobiol. 24 123 4) Doble (1996), The pharmacology and mechanism of action of riluzole; Neurology 47 S233 5) Pittenger et al. (2008), Riluzole in the treatment of mood and anxiety disorders; CNS Drugs 22 761 6) Namkoong et al. (2007), Metabotropic glutamate receptor 1 and glutamate signaling in human melanoma; Cancer Res. 67 2298 7) Zhang et al. (2015), Anti-cancer effect of metabotropic glutamate receptor inhibition in human glioma U87 cells: involvement of PI3K/Akt/mTOR pathway; Cell Physiol. Biochem. 35 419 8) Sperling et al. (2017), Riluzole: a potential therapeutic intervention in human brain tumor stem-like cells; Oncotarget 8 96697