DISPOSITION OF FLUVOXAMINE IN HUMANS IS DETERMINED BY THE POLYMORPHICCYP2D6 AND ALSO BY THE CYP1A2 ACTIVITY

Background: Fluvoxamine is a selective serotonin reuptake inhibitor us ed widely in the treatment of depression and other psychiatric disease s, but little is known about the specific isozymes involved in its met abolism, This study investigated the relationship between fluvoxamine disposition and the polymorphic CYP2D6 and the polycyclic aromatic hyd rocarbon (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 assesse d in plasma by high performance liquid chromatography, five of the ext ensive metabolizers and one of the poor metabolizers were smokers of m ore than 10 cigarettes per day. The CYP1A2 activity was determined by means of a urinary caffeine test. Results: Compared with nonsmoking ex tensive metabolizers, nonsmoking poor metabolizers had a statistically significant (p=0.02, Mann-Whitney U test) about twofold higher maximu m plasma concentration, longer half-life, and fivefold lower oral clea rance of fluvoxamine, The oral clearance of fluvoxamine correlated to the CYP1A2 index in the 14 subjects (r(s)=0.58; p <0.05; Spearman rank correlation). Conclusion: The disposition of fluvoxamine in humans is associated with the polymorphic CYP2D6 activity, but CYP1A2 also seem s to be involved.