Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis.
OBJECTIVE
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.
van Kan
H J M
HJ
Academic Medical Centre, Department of Clinical Pharmacy, Meibergdreef 9, PO Box 22660, 1100 DD Amsterdam, The Netherlands. h.j.vankan@amc.uva.nl
Groeneveld
G J
GJ
Kalmijn
S
S
Spieksma
M
M
van den Berg
L H
LH
Guchelaar
H J
HJ
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000201:enzymology*; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002110:Caffeine / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019782:Riluzole / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013806:Theophylline / Q000378:metabolism
D000927:Anticonvulsants; D002110:Caffeine; D019782:Riluzole; D013806:Theophylline; D019388:Cytochrome P-450 CYP1A2; C021183:1,7-dimethylxanthine