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

Aims Riluzole 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 a...

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Bibliographic Details
Published in:British journal of clinical pharmacology 2005-03, Vol.59 (3), p.310-313
Main Authors: Van Kan, H. J. M., Groeneveld, G. J., Kalmijn, S., Spieksma, M., Van Den Berg, L. H., Guchelaar, H. J.
Format: Article
Language:English
Subjects:
Administration, Oral
Adolescent
Adult
Aged
Amyotrophic Lateral Sclerosis - drug therapy
Amyotrophic Lateral Sclerosis - enzymology
Anticonvulsants - pharmacokinetics
Anticonvulsants - therapeutic use
Biological and medical sciences
Caffeine - metabolism
CYP1A2
Cytochrome P-450 CYP1A2 - metabolism
Female
Humans
Male
Medical sciences
metabolism
Middle Aged
neuromuscular disease
pharmacokinetics
Pharmacokinetics/Dosing/Disposition
Pharmacology. Drug treatments
riluzole
Riluzole - pharmacokinetics
Riluzole - therapeutic use
Theophylline - metabolism
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Summary:Aims Riluzole 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. Methods A 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. Results Riluzole 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 r2 = 0.369). Conclusions The 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.
ISSN:0306-5251
1365-2125
DOI:10.1111/j.1365-2125.2004.02233.x