Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.
Pharmacol Rep. 2011;63(6):1491-9. doi: 10.1016/s1734-1140(11)70713-7.
The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the activity of cytochrome P450 2C11 (CYP2C11), measured as a rate of testosterone 2α- and 16α-hydroxylation. The reaction was studied in control liver microsomes in the presence of neuroleptics, as well as in the microsomes of rats treated intraperitoneally (ip) with pharmacological doses of the drugs (promazine, levomepromazine, thioridazine and perazine 10 mg/kg; chlorpromazine 3 mg/kg; haloperidol 0.3 mg/kg; risperidone 0.1 mg/kg; sertindole 0.05 mg/kg) for one day or two weeks (twice a day), in the absence of the neuroleptics in vitro. The investigated neuroleptics added to control liver microsomes produced some inhibitory effects on CYP2C11 activity, which were moderate (thioridazine: K(i) = 55), modest (sertindole and perazine: K(i) = 76 and 94 μM, respectively) or week (promazine, levomepromazine, haloperidol and chlorpromazine: K(i) = 285, 280, 223 and 157 μM, respectively). Risperidone had the weakest inhibitory effect on the CYP2C11 activity (K(i) = 641 μM). One-day exposure of rats to the neuroleptics did not significantly change the activity of CYP2C11 in liver microsomes. Of the neuroleptics studied, only chronic treatment with levomepromazine, perazine and thioridazine diminished CYP2C11 activity; those effects were positively correlated with the observed decreases in the protein level of the enzyme. The in vivo inhibition of CYP2C11 by chronic treatment with the three phenothiazines suggests their influence on the enzyme regulation. A possible mechanism of CYP2C11 regulation by the neuroleptics and its pharmacological significance are discussed.
本研究旨在探讨经典和非典型神经阻滞剂对细胞色素 P450 2C11（CYP2C11）活性的影响，以睾酮 2α-和 16α-羟化的速率来衡量。在存在神经阻滞剂的情况下，在对照肝微粒体中以及在腹腔内（ip）用药物剂量（奋乃静、左美丙嗪、硫利达嗪和哌嗪 10mg/kg；氯丙嗪 3mg/kg；氟哌啶醇 0.3mg/kg；利培酮 0.1mg/kg；司来吉兰 0.05mg/kg）治疗一天或两周（每天两次）的大鼠的微粒体中研究了该反应，在体外没有神经阻滞剂的情况下。研究中的神经阻滞剂添加到对照肝微粒体中对 CYP2C11 活性产生了一些抑制作用，这些抑制作用是中等强度的（硫利达嗪：K(i) = 55）、适度的（司来吉兰和哌嗪：K(i) = 76 和 94μM，分别）或弱的（奋乃静、左美丙嗪、氟哌啶醇和氯丙嗪：K(i) = 285、280、223 和 157μM，分别）。利培酮对 CYP2C11 活性的抑制作用最弱（K(i) = 641μM）。大鼠一天接触神经阻滞剂不会显著改变肝微粒体中 CYP2C11 的活性。在所研究的神经阻滞剂中，只有慢性给予左美丙嗪、哌嗪和硫利达嗪会降低 CYP2C11 的活性；这些作用与观察到的酶蛋白水平下降呈正相关。三种吩噻嗪类药物慢性治疗对 CYP2C11 的体内抑制作用表明它们对酶调节的影响。讨论了神经阻滞剂对 CYP2C11 调节的可能机制及其药理学意义。
