Riluzole metabolism and CYP1A1/2 polymorphisms in patients with ALS.
Riluzole is the only FDA approved drug for the treatment of amyotrophic lateral sclerosis. Riluzole is assumed to be mainly metabolized by the liver cytochrome CYP1A2 and by the extra-hepatic cytochrome CYP1A1. CYP1A2 and CYP1A1 genetic polymorphisms are known, but their relationship to riluzole metabolism in ALS patients has not been investigated. The aim of this study was to determine whether the polymorphisms of the CYP1A2 and the CYP1A1 genes in ALS patients are associated with riluzole metabolic profiles. Thirty-two patients with a diagnosis of probable or definite ALS and who were on riluzole, participated in the study. Trough and peak plasma riluzole levels were measured using analytical chromatography-mass spectrometry methods. Association of the genotypes of the SNPs spanning the CYP1A1 and CYP1A2 genes (including one SNP in the intergenic region) with mean riluzole peak and trough levels was studied using ANOVA and Tukey's HSD. The mean peak riluzole level was 202+/-111 ng/ml and mean trough level 54.3+/-37.5 ng/ml. Our data do not support any association of the four CYP1A1 and CYP1A2 polymorphisms with the riluzole metabolic profile. In conclusion, genetic variations in CYP1A1 and CYP1A2 genes do not seem to influence riluzole levels. Further work is needed to better understand the genetic regulation of CYP1A enzymes and their role in riluzole metabolism.
Ajroud-Driss
Senda
S
Davee Department of Neurology and Clinical Neurosciences, Northwestern University Institute of Neuroscience, Chicago, Illinois 60611, USA. s-ajroud@md.northwestern.edu
Saeed
Mohammad
M
Khan
Humaira
H
Siddique
Nailah
N
Hung
W Y
WY
Sufit
Robert
R
Heller
Scott
S
Armstrong
Jennifer
J
Casey
Pat
P
Siddique
Teepu
T
Lukas
Thomas J
TJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*; D000704:Analysis of Variance; D002851:Chromatography, High Pressure Liquid; D002895:Chromosomes, Human, Pair 5; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000097:blood* / Q000627:therapeutic use; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D019782:Riluzole / Q000097:blood* / Q000627:therapeutic use
D018696:Neuroprotective Agents; D019782:Riluzole; C504573:CYP1A2 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2