P-glycoprotein mediates the pharmacokinetic interaction of olanzapine with fluoxetine in rats.
P-glycoprotein mediates the pharmacokinetic interaction of olanzapine with fluoxetine in rats.
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P-糖蛋白介导奥氮平与氟西汀在大鼠体内的药代动力学相互作用。
DOI：
10.1016/j.taap.2021.115735
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发表时间：
2021-10
影响因子：
3.8
通讯作者：
Wang Xin
中科院分区：
文献类型：
--
作者：
Xu Yuan;Lu Jian;Yao Bingyi;Zhang Yuanjin;Huang Shengbo;Liu Jie;Zhang Yanfang;Guo Yuanqing;Wang Xin
奥氮平联合氟西汀(奥氮平/氟西汀联合，OFC)治疗难治性抑郁症的临床试验显示疗效显著，但它们之间的药物相互作用(DDI)尚不清楚。本文研究了奥氮平和氟西汀在野生型(WT)和MDR1a/b基因敲除(KO)大鼠体内的药代动力学相互作用。通过分析奥氮平单次给药和联合给药的药代动力学和组织分布，探讨P-gp介导的DDI潜力。结果表明，在WT大鼠中，氟西汀联合用药增加了奥氮平的峰值浓度(Cmax，联用组为44.1g/mLvs9.0±11.5 ng/mLvs9.0±11.5 ng/mLvs.AUC0-t，235.8±22.7ng.h×10 ng/mLvs47.5±88.4ng.h×1gg/mL.CL，联合组为8119.0±677.9.1cmL/h/kg)，降低了清除量(cL值，联合组为49.469.0cmL/h/kgvs49,469.0cmL/h/kg)。同时，氟西汀显著增加奥氮平在WT大鼠脑、肝、肾和回肠的活体暴露，提示DDI的发生。在体外培养的Caco-2细胞中也观察到同样的现象。然而，在KO大鼠中，单一治疗组和联合治疗组之间的药代动力学参数没有显著差异。结论：P-gp在奥氮平和氟西汀大鼠体内的药代动力学相互作用中起重要作用。本研究可为奥氮平联合氟西汀的临床安全性提供参考。
Clinical trials of olanzapine combined with fluoxetine (Olanzapine/Fluoxetine Combination, OFC) in the treatment of refractory depression have shown significant efficacy, but the drug-drug interaction (DDI) between them remains unclear. In this report, the pharmacokinetic interaction between olanzapine and fluoxetine was studied in wild-type (WT) andMdr1a/bgene knockout (KO) rats. By analyzing the pharmacokinetics and tissue distribution of olanzapine in single dose and combination, the potential DDI mediated by P-gp was explored. The results showed that in WT rats, the combination of fluoxetine increased the peak concentration (Cmax, 44.1 ± 5.1 ng/mL in the combination groupvs9.0 ± 1.5 ng/mL in the monotherapy group) and the exposure (AUC0-t, 235.8 ± 22.7 h × ng/mL in the combination groupvs47.5 ± 8.4 h × ng/mL in monotherapy group) of olanzapine, and decreased the clearance (CL, 8119.0 ± 677.9 mL/h/kg in the combination groupvs49,469.0 ± 10,306.0 mL/h/kg in monotherapy group). At the same time, fluoxetine significantly increased thein vivoexposure of olanzapine in brain, liver, kidney and ileum of WT rats, indicating the occurrence of DDI. The same phenomenon was observed in Caco-2 cellsin vitroas well. However, in KO rats, there was no significant difference in pharmacokinetic parameters between the monotherapy group and the combination group. In conclusion, P-gp plays an important role in the pharmacokinetic interaction between olanzapine and fluoxetine in rats. This study may provide a reference for the clinical safety of olanzapine combined with fluoxetine.
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影响因子：
10.6
作者：
M. Seager;K. Huff;V. Barth;L. Phebus;K. Rasmussen
通讯作者：
M. Seager;K. Huff;V. Barth;L. Phebus;K. Rasmussen
影响因子：
3.7
作者：
J. Pardo;S. Sheikh;G. Schwindt;Joel T. Lee;D. Adson;Barry R. Rittberg;F. Abuzzahab
通讯作者：
J. Pardo;S. Sheikh;G. Schwindt;Joel T. Lee;D. Adson;Barry R. Rittberg;F. Abuzzahab
DOI：
--
发表时间：
2001-06
期刊：
The Journal of clinical psychiatry
影响因子：
--
作者：
D. B. Allison;D. Casey
通讯作者：
D. B. Allison;D. Casey
DOI：
--
发表时间：
1997-02
期刊：
The Journal of clinical psychiatry
影响因子：
--
作者：
C. Beasley;G. Tollefson;P. Tran
通讯作者：
C. Beasley;G. Tollefson;P. Tran
影响因子：
6.1
作者：
Boulton, DW;DeVane, CL;Markowitz, JS
通讯作者：
Markowitz, JS