节点文献

CYP 2D6、CYP3A5和MDR1基因多态性与利培酮代谢的相关性研究

Correlation of genetic polymorphism of CYP 2D6,CYP3A5 and MDR1 with resperidone metabolism

  • 推荐 CAJ下载
  • PDF下载
  • 不支持迅雷等下载工具,请取消加速工具后下载。

【作者】 向倩赵侠周颖孙培红梁雁段京莉崔一民

【Author】 XIANG Qian~1,ZHAO Xia~1,ZHOU Ying~1,SUN Pei-hong~1,LIANG Yan~1,DUAN Jing-li~2,CUI Yi-min~1 (1 Peking University First Hospital,Beijing 100034,China;2 Peking University Third Hospital,Beijing 100083, China)

【机构】 北京大学第一医院北京大学第三医院

【摘要】 目的临床研究显示利培酮和它的总活性物(利培酮与其活性代谢产物9-羟基利培酮之和)与利培酮治疗的疗效和不良反应相关。而以往的研究和药物浓度监测发现,利培酮和总活性物的血药浓度存在较大个体差异。本研究的目的是在中国健康志愿者中,评估代谢酶和转运蛋白(P-糖蛋白)基因多态性对利培酮和总活性物药代动力学的影响。方法 :23名健康受试者单次口服2毫克利培酮,分别在0、0.25、0.5、0.75、1、1.5、2、3、4、6、8、12、24、36、48、72和96小时采集血样,测定利培酮和9-羟基利培酮血药浓度,并测定每个受试者CYP2D6、CYP3A5*3、MDR1 C3435T和G2677T/A基因型。结果 :利培酮的最大血药浓度(Cmax)利体内总暴露量(AUC(0-96))与CYP2D6*10相关,携带纯合子CYP2D6*10的受试者利培酮体内暴露量远高于携带CYP2D6*1/*1或*1/*10者(p<0.05)。同时携带CYP2D6*10/*10和CYP3A5*3/*3基因型者与其他受试者相比,AUC(0-96)高97%,Cmax高59%(p<0.05)。在本试验还中发现,MDR1 2677GA基因型可能影响利培酮的吸收,因为携带MDR1 2677GA者Tmax显著高于其他MDR1基因型的受试者(p<0.05)。结论 :CYP2D6*10基因型能够解释利培酮母体药物在体内的代谢差异,同时本研究首次发现了与利培酮总活性物药代动力学相关的基因多态性,并发现MDR1 2677GA基因型可能影响利培酮的代谢,为利培酮个体化治疗提供了重要的药代动力学证据。

【Abstract】 OBJECTIVE Clinical studies suggest that plasma levels of risperidone and its active moiety (risperidone + 9-hydroxyrisperidone) correlate with adverse drug effects.The aim of this study was to evaluate the pharmacogenetic variability in the disposition of risperidone and the active moiety in healthy Chinese subjects. METHODS Two milligrams of risperidone was orally administered to 23 healthy chinese subjects,and blood samples were taken after dosing.We determined the polymorphic alleles of CYP2D6*4,*5,*10,*14A, CYP3A5*3 and MDR1 C1236T,G2677TA,C3435T in each subject.The whole blood concentration of risperidone and 9-hydroxyrisperidone were measured by an High performance liquid chromatography/tandem mass spectrometry(HPLC-MS/MS.RESULTS The mean maximum plasma concentration(C(max)) and AUC extrapolated to infinity(AUC(0-96)) for risperidone were significantly higher in subjects possessing the CYP2D6*10 allele than in those with the CYP2D6*1/*1 and *1/*10 genotype.For active moiety,the subjects carried both homozygous CYP2D6*10 and homozygous CYP3A5*3 had 97%higher AUC(0-96) and 59%higher Cmax compared with other CYP2D6 EM subjects.The MDR1 2677GA genotype may also play a role in risperidone pharmacokinetics.CONCLUSION The metabolism of risperidone and its active moiety were influenced by CYP2D6*10,CYP3A5*3 and MDR1 2677GA genotypes.Further studies are needed to explore the impact of MDR1 2677GA and CYP3A5 polymorphisms on risperidone therapy.

【关键词】 利培酮中国人CYP2D6CYP3A5MDR1
【Key words】 risperidoneChineseCYP2D6CYP3A5MDR1
  • 【会议录名称】 2010施慧达杯第十届全国青年药学工作者最新科研成果交流会论文集
  • 【会议名称】2010施慧达杯第十届全国青年药学工作者最新科研成果交流会
  • 【会议时间】2010-07-01
  • 【会议地点】中国吉林长春
  • 【分类号】R96
  • 【主办单位】中国药学会(Chinese Pharmaceutical Association)
节点文献中: