Effect of smoking and CYP2D6 polymorphisms on the extent of fluvoxamine-alprazolam interaction in patients with psychosomatic disease.
OBJECTIVE
Fluvoxamine (FVX) is metabolized by cytochrome P450 (CYP) 2D6 and CYP1A2 and inhibits CYP3A4. The aim of this study was to investigate the factors responsible for interindividual variability in the extent of interaction between FVX and alprazolam (ALP).


METHODS
Blood samples were taken from 49 depressive patients to determine plasma concentration of FVX, ALP or both. Twenty-four samples were taken during the FVX-alone period, 21 samples during the ALP-alone period and 30 samples during the FVX-ALP period. Subjects were also genotyped for CYP2D6.


RESULTS
The concentration-to-dose (C/D) ratio of ALP during the FVX-treatment period was significantly higher than that during the ALP-alone period. The CYP2D6 genotype affected neither the C/D ratios of FVX nor the extent of interaction. The mean C/D ratio of FVX in smokers was reduced by more than 30% in comparison with that in non-smokers. The mean C/D ratio of ALP in non-smokers was increased by FVX, while that in smokers was unchanged.


CONCLUSIONS
The extent of interaction between FVX and ALP may be affected by smoking, which alters the C/D ratio of FVX. Therefore, when FVX and ALP are concomitantly administered, it should be noted that non-smokers may exhibit greater drug interaction than smokers.
Sugahara
Hideyo
H
Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Maebara
Chiharu
C
Ohtani
Hisakazu
H
Handa
Masanori
M
Ando
Katsumi
K
Mine
Kazunori
K
Kubo
Chiharu
C
Ieiri
Ichiro
I
Sawada
Yasufumi
Y
D000483:Alleles; D000525:Alprazolam / Q000097:blood / Q000627:therapeutic use*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000235:genetics; D016666:Fluvoxamine / Q000097:blood / Q000627:therapeutic use*; D005838:Genotype; D006801:Humans; D011110:Polymorphism, Genetic / Q000187:drug effects; D011602:Psychophysiologic Disorders / Q000188:drug therapy / Q000235:genetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000627:therapeutic use*; D012907:Smoking / Q000378:metabolism*
D000525:Alprazolam; D019389:Cytochrome P-450 CYP2D6; D016666:Fluvoxamine; D017367:Selective Serotonin Reuptake Inhibitors