Fang J, Bourin M, Baker G B
Department of Psychiatry, University of Alberta, Edmonton, Canada.
Naunyn Schmiedebergs Arch Pharmacol. 1999 Feb;359(2):147-51. doi: 10.1007/pl00005334.
Risperidone is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses. Formation of 9-hydroxyrisperidone, an active metabolite, is the most important metabolic pathway of risperidone in human. In the present study, in vitro metabolism of risperidone (100 microM) was investigated using the recombinant human cytochrome P450 (CYP) enzymes CYP1A1, CYP1A2, CYP2C8, CYP2C9-arg144, CYP2C9-cys144, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 supplemented with an NADPH-generating system. 9-Hydroxyrisperidone was determined by a new HPLC method with an Hypersil CN column and a UV detector. Of these enzymes, CYPs 2D6, 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9-hydroxyrisperidone, with activities of 7.5, 0.4 and 0.2 pmol pmol(-1) CYP min(-1), respectively. A correlation study using a panel of human liver microsomes showed that the formation of 9-hydroxyrisperidone is highly correlated with CYP2D6 and 3A activities. Thus, both CYP2D6 and 3A4 are involved in the 9-hydroxylation of risperidone at the concentration of risperidone used in this study. This observation is confirmed by the findings that both quinidine (inhibitor of CYP2D6) and ketoconazole (inhibitor of CYP3A4) can inhibit the formation of 9-hydroxyrisperidone. Furthermore, inducers of CYP can significantly increase the formation of 9-hydroxyrisperidone in rat. The formation of 9-hydroxyrisperidone is highly correlated with testosterone 6beta-hydroxylase activities, suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat.
利培酮是一种相对较新的抗精神病药物，据报道它可改善精神分裂症的阳性和阴性症状，并且在低剂量时产生的锥体外系副作用相对较少。9-羟基利培酮作为一种活性代谢产物，其形成是利培酮在人体内最重要的代谢途径。在本研究中，使用重组人细胞色素P450（CYP）酶CYP1A1、CYP1A2、CYP2C8、CYP2C9-arg144、CYP2C9-cys144、CYP2C19、CYP2D6、CYP3A4和CYP3A5并辅以NADPH生成系统，对利培酮（100微摩尔）的体外代谢进行了研究。采用配备Hypersil CN柱和紫外检测器的新型高效液相色谱法测定9-羟基利培酮。在这些酶中，发现CYP 2D6、3A4和3A5能够将利培酮代谢为9-羟基利培酮，其活性分别为7.5、0.4和0.2皮摩尔皮摩尔⁻¹ CYP分钟⁻¹。使用一组人肝微粒体进行的相关性研究表明，9-羟基利培酮的形成与CYP2D6和3A活性高度相关。因此，在本研究使用的利培酮浓度下，CYP2D6和3A4均参与利培酮的9-羟化反应。奎尼丁（CYP2D6抑制剂）和酮康唑（CYP3A4抑制剂）均可抑制9-羟基利培酮的形成，这一发现证实了该观察结果。此外，CYP诱导剂可显著增加大鼠体内9-羟基利培酮的形成。9-羟基利培酮的形成与睾酮6β-羟化酶活性高度相关，表明诱导型CYP3A对大鼠体内利培酮的代谢有显著贡献。
