抗抑郁药物对大鼠肝脏细胞色素 P450 2C11（CYP2C11）的影响。

Effect of antidepressant drugs on cytochrome P450 2C11 (CYP2C11) in rat liver.

机构信息

Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.

出版信息

Pharmacol Rep. 2013;65(5):1247-55. doi: 10.1016/s1734-1140(13)71482-8.

DOI:10.1016/s1734-1140(13)71482-8

PMID:24399720

Abstract

BACKGROUND

Rat CYP2C11 (besides CYP2C6) can be regarded as a functional counterpart of human CYP2C9. The aim of the present study was to investigate the influence of classic and novel antidepressant drugs on the activity of CYP2C11, measured as a rate of testosterone 2α and 16α-hydroxylation.

METHODS

The reaction was studied in control liver microsomes in the presence of antidepressants, as well as in microsomes from rats treated intraperitoneally (ip) with pharmacological doses of the tested drugs (imipramine, amitriptyline, clomipramine, nefazodone - 10 mg/kg ip; desipramine, fluoxetine, sertraline - 5 mg/kg ip; mirtazapine - 3 mg/kg ip) for one day or two weeks (twice a day), in the absence of antidepressants in vitro.

RESULTS

The investigated antidepressant drugs added to control liver microsomes produced certain inhibitory effects on CYP2C11 activity, which were moderate (sertraline, nefazodone and clomipramine: Ki = 39, 56 and 66 μM, respectively), modest (fluoxetine and amitriptyline: Ki = 98 and 108 μM, respectively) or weak (imipramine and desipramine: Ki = 191 and 212 μM, respectively). Mirtazapine had no inhibitory effect on CYP2C11 activity. One-day exposure of rats to the antidepressant drugs did not significantly change the activity of CYP2C11 in liver microsomes; however, imipramine, desipramine and fluoxetine showed a tendency to diminish the activity of CYP2C11. Of the antidepressants studied, only desipramine and fluoxetine administered chronically elevated CYP2C11 activity; those effects were positively correlated with the observed increases in the enzyme protein level.

CONCLUSION

Three different mechanisms of the antidepressants-CYP2C11 interaction are postulated: 1) a direct inhibition of CYP2C11 shown in vitro by nefazodone, SSRIs and TADs; 2) in vivo inhibition of CYP2C11 produced by one-day treatment with imipramine, desipramine and fluoxetine, which suggests inactivation of the enzyme by reactive metabolites; 3) in vivo induction of CYP2C11 produced by chronic treatment with desipramine and fluoxetine, which suggests their influence on enzyme regulation.

摘要

背景

大鼠 CYP2C11（除 CYP2C6 外）可被视为人类 CYP2C9 的功能对应物。本研究的目的是研究经典和新型抗抑郁药对 CYP2C11 活性的影响，其活性通过睾酮 2α 和 16α-羟化率来衡量。

方法

在存在抗抑郁药的情况下，在对照肝微粒体中以及在腹腔内（ip）给予药理学剂量的测试药物（丙咪嗪、阿米替林、氯米帕明、奈法唑酮-10 mg/kg ip；去甲丙咪嗪、氟西汀、舍曲林-5 mg/kg ip；米氮平-3 mg/kg ip）的大鼠的微粒体中研究了该反应，体外无抗抑郁药。

结果

加入对照肝微粒体的研究性抗抑郁药对 CYP2C11 活性产生了一定的抑制作用，这些抑制作用中等（舍曲林、奈法唑酮和氯米帕明：Ki 分别为 39、56 和 66 μM）、适度（氟西汀和阿米替林：Ki 分别为 98 和 108 μM）或弱（丙咪嗪和去甲丙咪嗪：Ki 分别为 191 和 212 μM）。米氮平对 CYP2C11 活性没有抑制作用。大鼠一天接触抗抑郁药不会显著改变肝微粒体中 CYP2C11 的活性；然而，丙咪嗪、去甲丙咪嗪和氟西汀表现出降低 CYP2C11 活性的趋势。在所研究的抗抑郁药中，只有去甲丙咪嗪和氟西汀长期给药可升高 CYP2C11 活性；这些作用与观察到的酶蛋白水平升高呈正相关。

结论

提出了抗抑郁药-CYP2C11 相互作用的三种不同机制：1）体外由奈法唑酮、SSRIs 和 TADs 直接抑制 CYP2C11；2）在体内通过一天治疗丙咪嗪、去甲丙咪嗪和氟西汀抑制 CYP2C11，提示酶被反应性代谢物失活；3）通过长期用去甲丙咪嗪和氟西汀治疗在体内诱导 CYP2C11，提示它们对酶调节的影响。