8-Hydroxylation and Glucuronidation of Mirtazapine in Japanese Psychiatric Patients: Significance of the Glucuronidation Pathway of 8-Hydroxy-Mirtazapine
8-Hydroxylation and Glucuronidation of Mirtazapine in Japanese Psychiatric Patients: Significance of the Glucuronidation Pathway of 8-Hydroxy-Mirtazapine
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日本精神病患者中米氮平的 8-羟基化和葡萄糖醛酸化：8-羟基米氮平葡萄糖醛酸化途径的意义
DOI：
10.1055/a-0918-6408
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发表时间：
2019
影响因子：
4.3
通讯作者：
Shimoda Kazutaka
中科院分区：
文献类型：
--
作者：
Shinozaki Masataka;Pierce Jason;Hayashi Yuki;Watanabe Takashi;Sasaki Taro;Komahashi-Sasaki Hazuki;Akiyama Kazufumi;Kato Kazuko;Inoue Yoshimasa;Tsuchimine Shoko;Yasui-Furukori Norio;Ozeki Yuji;Shimoda Kazutaka
为了解米氮平(MIR)在日本精神病人体内的代谢情况，我们测定了79例日本精神病人MIR、N-脱甲基米氮平(DMIR)、8-羟基米氮平(8-OH-MIR)、米氮平葡萄糖醛酸苷(MIR-G)和8-羟基米氮平葡萄糖醛酸苷(8-OH-MIR-G)的血浆浓度，以达到稳态血药浓度。用高效液相色谱法测定血浆MIR、DMIR和8-OH-MIR的水平。血浆中MIR-G和8-OH-MIR的浓度分别由总MIR和总8-OH-MIR(即 )减去未结合的MIR和未结合的8-OH-MIR来确定。结果血浆8-OH-MIR水平明显低于MIR和DMIR(中位数分别为1.42nmo1/L、92.71nmo1/L和44.96nmo1/L)。血浆MIR-G和8-OH-MIR-G水平(中位数)分别为75.00nmol/L和111.60 /L，MIR-G/MIR和8-OH-MIR-G/8-OH-MIR的比值分别为0.92和59.5。多元回归分析显示，吸烟与血浆MIR浓度(剂量和体重校正，p=0.040)相关，年龄(年龄)与血浆DMIR浓度(剂量和体重校正，p=0.018)显著相关。结论8-OH-MIR的血浆浓度低至1.42n /L，而8-OH-MIR-G的血药浓度约为8-OH-MIR的59.5倍，提示MIR的羟基化及其糖醛酸化在日本人群中具有显著的作用。
IntroductionTo 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).MethodsSeventy-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.ResultsPlasma 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.DiscussionThe 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.