8-Hydroxylation and Glucuronidation of Mirtazapine in Japanese Psychiatric Patients: Significance of the Glucuronidation Pathway of 8-Hydroxy-Mirtazapine

Masataka Shinozaki; Jason Pierce; Yuki Hayashi; Takashi Watanabe; Taro Sasaki; Hazuki Komahashi-Sasaki; Kazufumi Akiyama; Kazuko Kato; Yoshimasa Inoue; Shoko Tsuchimine; Norio Yasui-Furukori; Yuji Ozeki; Kazutaka Shimoda

doi:10.1055/a-0918-6408

Pharmacopsychiatry, Inhaltsverzeichnis

Pharmacopsychiatry 2019; 52(05): 237-244
DOI: 10.1055/a-0918-6408

Original Paper

8-Hydroxylation and Glucuronidation of Mirtazapine in Japanese Psychiatric Patients: Significance of the Glucuronidation Pathway of 8-Hydroxy-Mirtazapine

Masataka Shinozaki

¹Department of Psychiatry, Dokkyo Medical University School of Medicine, Tochigi, Japan

,

Jason Pierce

¹Department of Psychiatry, Dokkyo Medical University School of Medicine, Tochigi, Japan

³Virginia Mason Medical Center, Seattle, Washington, USA

⁴College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA

,

Yuki Hayashi

¹Department of Psychiatry, Dokkyo Medical University School of Medicine, Tochigi, Japan

,

Takashi Watanabe

¹Department of Psychiatry, Dokkyo Medical University School of Medicine, Tochigi, Japan

,

Taro Sasaki

¹Department of Psychiatry, Dokkyo Medical University School of Medicine, Tochigi, Japan

,

Hazuki Komahashi-Sasaki

¹Department of Psychiatry, Dokkyo Medical University School of Medicine, Tochigi, Japan

,

Kazufumi Akiyama

²Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Tochigi, Japan

,

Kazuko Kato

⁵Sakura La Mental Clinic, Tochigi, Japan

,

Yoshimasa Inoue

¹Department of Psychiatry, Dokkyo Medical University School of Medicine, Tochigi, Japan

,

Shoko Tsuchimine

⁶Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

⁷Department of Neuropsychiatry, Hirosaki University Graduate School of Medicine, Aomori, Japan

,

Norio Yasui-Furukori

¹Department of Psychiatry, Dokkyo Medical University School of Medicine, Tochigi, Japan

⁷Department of Neuropsychiatry, Hirosaki University Graduate School of Medicine, Aomori, Japan

,

Yuji Ozeki

¹Department of Psychiatry, Dokkyo Medical University School of Medicine, Tochigi, Japan

⁸Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan

,

Kazutaka Shimoda

¹Department of Psychiatry, Dokkyo Medical University School of Medicine, Tochigi, Japan

› Institutsangaben

Abstract

Introduction To investigate the metabolism of mirtazapine (MIR) in Japanese psychiatric patients, we determined the plasma levels of MIR, N-desmethylmirtazapine (DMIR), 8-hydroxy-mirtazapine (8-OH-MIR), mirtazapine glucuronide (MIR-G), and 8-hydroxy-mirtazapine glucuronide (8-OH-MIR-G).

Methods Seventy-nine Japanese psychiatric patients were treated with MIR for 1–8 weeks to achieve a steady-state concentration. Plasma levels of MIR, DMIR, and 8-OH-MIR were determined using high-performance liquid chromatography. Plasma concentrations of MIR-G and 8-OH-MIR-G were determined by total MIR and total 8-OH-MIR (i. e., concentrations after hydrolysis) minus unconjugated MIR and unconjugated 8-OH-MIR, respectively. Polymerase chain reaction was used to determine CYP2D6 genotypes.

Results Plasma levels of 8-OH-MIR were lower than those of MIR and DMIR (median 1.42 nmol/L vs. 92.71 nmol/L and 44.96 nmol/L, respectively). The plasma levels (median) of MIR-G and 8-OH-MIR-G were 75.00 nmol/L and 111.60 nmol/L, giving MIR-G/MIR and 8-OH-MIR-G/8-OH-MIR ratios of 0.92 and 59.50, respectively. Multiple regression analysis revealed that smoking was correlated with the plasma MIR concentration (dose- and body weight–corrected, p=0.040) and that age (years) was significantly correlated with the plasma DMIR concentration (dose- and body weight–corrected, p=0.018). The steady-state plasma concentrations of MIR and its metabolites were unaffected by the number of CYP2D6*5 and CYP2D6*10 alleles.

Discussion The plasma concentration of 8-OH-MIR was as low as 1.42 nmol/L, whereas 8-OH-MIR-G had an approximate 59.50 times higher concentration than 8-OH-MIR, suggesting a significant role for hydroxylation of MIR and its glucuronidation in the Japanese population.

Key words

mirtazapine - hydroxylation - glucuronidation - pharmacokinetics - pharmacogenetics

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Referenzen

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