Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis

Abstract

AimsRiluzole is used in a fixed dosing schedule of 50 mg twice daily to treat patients with amyotropic lateral sclerosis (ALS), one form of motor neurone disease. The large variability in the pharmacokinetics of riluzole may be a factor contributing to its limited therapeutic benefit. Riluzole is assumed to be mainly metabolized by the cytochrome P450 enzyme 1A2 (CYP1A2). The aim of the study was to investigate the relationship between CYP1A2 activity and riluzole clearance with a view to optimize drug treatment. MethodsA group of 30 ALS patients participated in the study. In each patient the CYP1A2 activity was determined using caffeine as a metabolic probe. Riluzole clearance was estimated from serum drug concentration measurements followed by Bayesian fitting. ResultsRiluzole clearance and the serum paraxanthine : caffeine (P/C) ratio showed a positive correlation ( r = 0.693; P = 0.0002). Linear regression analysis identified the P/C ratio (beta: 1.16) and height (beta: 0.027) as independent predictors of riluzole clearance (adjusted r 2 = 0.369). ConclusionsThe P/C ratio, used as measure of CYP1A2 activity, significantly correlated with the riluzole clearance, although only 37% of the observed variability could be explained.

Riluzole prodrugs for melanoma and ALS: Design, synthesis, and in vitro metabolic profiling

“…Riluzole is predominantly metabolized by the CYP1A2 isozyme 19 which is expressed heterogeneously in the population. This leads to variable bioavailability and drug exposure among patients with one report indicating riluzole exposure per kilogram of body weight at 48.7 µg-h/L/Kg with a standard deviation of 40.9 (189 patients).…”

Therapeutic progress in amyotrophic lateral sclerosis-beginning to learning

“…Thus slows down disease progression in SOD1 G93A transgenic mice [10] and significantly increase patient's survival by a few months [34]. However, riluzole demonstrates variable drug exposure which correlates with differential expression of cytochrome P450 isoform, CYP1A2 involved mainly in riluzole metabolism [35]. This high variability led to the development of more stable riluzole derivatives.…”

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

“…In vivo studies addressing the glucuronidation of riluzole are lacking. In a previous study in ALS patients using caffeine as a metabolic probe, it was found that differential CYP1A2 activity was responsible for 37% of the observed variability in riluzole clearance [10]. Therefore, alternative metabolic pathways, such as glucuronidation, may also play a role in the interindividual variability of riluzole elimination.…”