STEADY-STATE PLASMA-LEVELS OF NORTRIPTYLINE AND ITS 1.0-HYDROXY METABOLITE - RELATIONSHIP TO THE CYP2D6 GENOTYPE

The relationship between the CYP2D6 genotype and the steady state plas ma levels of nortriptyline (NT), its main active metabolite 10-hydroxy nortriptyline (10-OH-NT) and the NT/10-OH-NT ratio were studied in 21 Caucasian depressed patients treated with 100-150 mg NT daily. The pat ients had participated in a previously published study investigating t he role of NT and 10-OH-NT for the therapeutic effect of NT and the pl asma level data were from that study. In the present follow-up study, the patients were genotyped with respect to the polymorphic CYP2D6 by allele-specific PCR amplification and EcoRI RFLP. One poor metabolizer (PM) was identified and she had the highest plasma concentration of N T Among the 20 extensive metabolizers (EM), the genotype (homozygous v ersus heterozygous EM) alone was not found to explain the variance in dose-corrected NT concentrations, but contributed significantly when g ender was also taken into account. Together, these factors accounted f or 59% of the variability in NT levels. Female patients had higher pla sma levels of NT than male patients, 10-OH-NT levels were influenced b y genotype, and NT/10-OH-NT ratio by genotype and gender. The present follow-up study confirms a relationship between the CYP2D6 genotype an d the plasma levels of NT and its active metabolite. Identification of PM by genotyping should be of value for the prediction of the plasma levels and, consequently, the lower than average dose of NT required f or optimal therapy. Also among EM, the genotype contributes to the var iability in NT and 10-OH-NT levels but alone is of limited practical v alue for the prediction of optimal dosage.