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Dose-Dependent Effect of the CYP2D6 Genotype on the Steady-state Fluvoxamine Concentration

Watanabe, Junzo MD*; Suzuki, Yutaro MD, PhD*; Fukui, Naoki MD, PhD*; Sugai, Takuro MD*; Ono, Shin MD*; Inoue, Yoshimasa; Someya, Toshiyuki MD, PhD*

doi: 10.1097/FTD.0b013e31818d73b3
Original Article

Several studies have reported that the cytochrome P450 (CYP) 2D6 plays an important role in the fluvoxamine metabolism. However, some other studies have reported that the CYP2D6 genotype has no major impact on the fluvoxamine concentration. This study investigated the dose-dependent effect of CYP2D6-variant alleles on the steady-state fluvoxamine concentration. There were 23 patients whose plasma concentrations of fluvoxamine were measured at 4 doses (50, 100, 150, and 200 mg/d). The differences in the plasma fluvoxamine concentration were analyzed between 2 genotype groups divided by the number of CYP2D6-variant alleles (with 0 and 1 or 2 variant alleles). The results demonstrated the nonlinear kinetics of fluvoxamine metabolism, and the degree of nonlinear kinetics decreased as the dose was increased. Significant differences in fluvoxamine concentration were observed between the subjects with 0 variant alleles and the subjects with 1 or 2 variant alleles (P = 0.044) when they were treated by 50 mg of fluvoxamine. There were no significant differences in the plasma concentration of fluvoxamine at 100, 150, and 200 mg/d. The present study suggests that the effect of the CYP2D6 genotype on fluvoxamine metabolism is greater at lower doses of fluvoxamine.

From the *Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata; and †MP-Technopharma Corporation Technology Department, Fukuoka, Japan.

Received for publication July 7, 2008; accepted September 11, 2008.

Supported by Health and Labour Sciences Research Grants (Research on Psychiatric and Neurological Disease and Mental Health) (H17-kokoro-002) and by Grant-in-Aid for Young Scientists (B).

There are no conflicts of interest associated with this work.

Correspondence: Toshiyuki Someya, MD, PhD, Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-ichibancho, Niigata 951-8510, Japan (e-mail:

© 2008 Lippincott Williams & Wilkins, Inc.