Disposition of fluvoxamine in humans is determined by the polymorphic CYP2D6 and also by the CYP1A2 activity.
BACKGROUND
Fluvoxamine is a selective serotonin reuptake inhibitor used widely in the treatment of depression and other psychiatric diseases, but little is known about the specific isozymes involved in its metabolism. This study investigated the relationship between fluvoxamine disposition and the polymorphic CYP2D6 and the polycyclic aromatic hydrocarbon (as contained in cigarette smoke) inducible CYP1A2.


METHODS
Fluvoxamine (50 mg orally) was given to 10 extensive metabolizers and four poor metabolizers of debrisoquin, and concentrations were assessed in plasma by high performance liquid chromatography. Five of the extensive metabolizers and one of the poor metabolizers were smokers of more than 10 cigarettes per day. The CYP1A2 activity was determined by means of a urinary caffeine test.


RESULTS
Compared with nonsmoking extensive metabolizers, nonsmoking poor metabolizers had a statistically significant (p = 0.02, Mann-Whitney U test) about twofold higher maximum plasma concentration, longer half-life, and fivefold lower oral clearance of fluvoxamine. The oral clearance of fluvoxamine correlated to the CYP1A2 index in the 14 subjects (rs = 0.58; p < 0.05; Spearman rank correlation).


CONCLUSIONS
The disposition of fluvoxamine in humans is associated with the polymorphic CYP2D6 activity, but CYP1A2 also seems to be involved.
Carrillo
J A
JA
Department of Medical Laboratory Sciences and Technology, Huddinge Hospital, Sweden.
Dahl
M L
ML
Svensson
J O
JO
Alm
C
C
Rodríguez
I
I
Bertilsson
L
L
D018663:Adrenergic Agents / Q000493:pharmacokinetics; D000328:Adult; D002110:Caffeine / Q000493:pharmacokinetics; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D003647:Debrisoquin / Q000493:pharmacokinetics; D005260:Female; D016666:Fluvoxamine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D012907:Smoking / Q000097:blood
D018663:Adrenergic Agents; D002110:Caffeine; D000697:Central Nervous System Stimulants; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D003647:Debrisoquin; D016666:Fluvoxamine; D017367:Selective Serotonin Reuptake Inhibitors