Effect of tolterodine on sleep structure modulated by CYP2D6 genotype.
OBJECTIVE
Tolterodine, a drug for the treatment of overactive bladder symptoms, has a limited entry into the brain, which makes cognitive side effects seldom. However, some case reports have described central-nervous side effects such as sleepiness. The aim of this retrospective analysis was to investigate whether tolterodine-related effects on sleep stage parameters could be explained by different CYP2D6 metabolizer characteristics of subjects.


METHODS
Data were taken from two randomized, double-blind, placebo-controlled studies conducted in a cross-over design. Forty-eight volunteers underwent 4 two-night attended polysomnographic studies. Subjective quality of sleep and cognitive function were assessed. A single dose of 4 mg tolterodine or placebo was administered before sleep. Forty-four volunteers gave informed consent for genotyping. We found 19 extensive metabolizers (EM), 20 intermediate metabolizers (IM), 4 poor metabolizers (PM) and 1 ultrarapid metabolizer. There were no significant differences between the groups regarding demographic data.


RESULTS
Rapid eye movement (REM) sleep duration as a percentage of total sleep time showed significant reduction (p=0.019) in the group carrying one or more deficient alleles (IM+PM). No significant difference was found with two active alleles of CYP2D6 in the EM group. REM latencies under tolterodine displayed a tendency towards prolongation, which was irrespective of the metabolizer status. Subjective sleep parameters did not show statistically significant changes after tolterodine. Cognitive skills were not affected.


CONCLUSIONS
Our retrospective analysis reveals that a decrease of REM sleep under tolterodine is found only in individuals carrying one or two deficient CYP2D6 alleles.
Diefenbach
Konstanze
K
Institute of Clinical Pharmacology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Jaeger
Katrin
K
Wollny
Agnes
A
Penzel
Thomas
T
Fietze
Ingo
I
Roots
Ivar
I
D000328:Adult; D000368:Aged; D000483:Alleles; D001559:Benzhydryl Compounds / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D001711:Biotransformation / Q000235:genetics; D003408:Cresols / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004311:Double-Blind Method; D005260:Female; D020440:Gene Duplication; D005838:Genotype; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000235:genetics; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D010665:Phenylpropanolamine / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length / Q000235:genetics; D017286:Polysomnography / Q000187:drug effects; D016032:Randomized Controlled Trials as Topic; D012895:Sleep, REM / Q000187:drug effects*; D000068737:Tolterodine Tartrate
D001559:Benzhydryl Compounds; D003408:Cresols; D018727:Muscarinic Antagonists; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; D019389:Cytochrome P-450 CYP2D6