Population pharmacokinetics of riluzole in patients with amyotrophic lateral sclerosis

Abstract

The pharmacokinetics of riluzole has been characterized in patients during long-term therapy. Riluzole clearance is independent of dose and treatment duration. Within-patient variability is low. Gender and smoking status are the main covariates to explain interpatient variability.

Review of the Use of the Glutamate Antagonist Riluzole in Psychiatric Disorders and a Description of Recent Use in Childhood Obsessive-Compulsive Disorder

“…More than 90% of the drug is excreted in urine as metabolites, mainly as various glucuronides. Clearance of the drug is independent of dosage, but males and smokers (probably because of 1A2 induction) clear the drug faster than women and nonsmokers (Bruno et al 1997).…”

“…It has been shown that interindividual variation of riluzole serum level is much larger (by a factor of 50 times peak levels) than intraindividual variation (Bruno et al 1997;Groeneveld et al 2001). However, neither phenotypic variation in glucuronidation (UDT1A1*28 variability) ) nor P450 polymorphisms account for mean riluzole serum levels, at least in ALS patients.…”

The Glutamate Hypothesis in ALS: Pathophysiology and Drug Development

“…Some animal studies have found that, due to good lipid solubility and an efficient blood-brain barrier transporter, levels of riluzole are four-to six fold higher than blood levels after oral dosing, and that high levels can persist many hours after a single dose [108][109][110][111][112][113]. Riluzole is highly lipid soluble, with an octanol:water partition coefficient of 3,000:1 [114] and may enter brain in part by passive diffusion [113].…”

“…Riluzole is highly lipid soluble, with an octanol:water partition coefficient of 3,000:1 [114] and may enter brain in part by passive diffusion [113].…”

Pharmacokinetics of riluzole: evidence for glucuronidation as a major metabolic pathway not associated with UGT1A1 genotype

“…Pharmacokinetic studies of riluzole show a large variability of the drug's clearance and serum concentrations [6,7]. This was reconfirmed in a Dutch patient cohort evaluating the interindividual variability of riluzole peak (74%) and trough (58%) serum concentrations [7].…”