联苯双酯对环孢素A药代动力学的影响及其机制的遗传药理学研究
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摘要
遗传药理学研究发现,药物代谢酶和转运体是决定药物体内过程的关键因素,其活性的改变是导致药物相互作用的主要机制。药物代谢酶和转运体的遗传多态性是导致药物相互作用个体差异的重要决定因素。
环孢素A属于钙调磷酸酶抑制剂家族,主要通过特异性抑制淋巴细胞反应和增生发挥抑制免疫排斥的功效。目前临床上,环孢素A广泛的应用于器官移植术后免疫排斥反应的预防与治疗,该药物在疗效发挥的同时,表现出明显的药物代谢动力学个体差异以及狭窄的治疗窗,由于药物相互作用导致的毒副反应也十分常见。目前的研究证实,环孢素A在人体内的代谢、转运以及与之相关的药物相互作用的发生均与CYP3A4以及P糖蛋白的活性密切相关。针对环孢素A在人体内的药代学以及药效学个体差异所开展的研究也多围绕上述两个功能蛋白开展。
细胞色素P450(CYP450)酶系由基因超家族编码的酶蛋白组成,参与各种内源性以及外源性物质的生物转化。其中,CYP3A4是P450家族中的重要成员,主要表达在肝脏与小肠,参与了临床50%以上药物的代谢,是环孢素A在人体内生物转化过程中最重要的功能蛋白。目前的研究认为,药物对CYP3A4活性的影响,是导致环孢素A相关药物相互作用的主要原因之一。CYP3A4作为机体重要功能蛋白的一种,其活性在基础状态下也存在显著的个体差异。CYP3A4*18B是由日本学者发现的具有功能意义的突变位点.最近的研究发现,该位点的突变与环孢素A在机体内的药代动力学的个体差异密切相关。其中,基因型为CYP3A4*18突变型纯合子的受试者体内环孢素A的代谢显著加强。
P—糖蛋白是由多药耐药基因MDR1编码的一种能量依赖型药物外排泵,在肝脏、小肠、肾脏等人体的多种组织中都有分布。对于各种药物在人体的吸收、分布与消除均发挥重要作用。P—糖蛋白活性的高低与环孢素A在机体代谢的个体差异有着直接的联系。
核受体中的孕烷X受体(pregnane X receptor,PXR)核组成性雄烷受体(constitutive androstane receptor,CAR)对多种CYP450代谢酶以及转运体的转录调节发挥重要作用。目前,利用表达PXR或CAR的CYP450酶以及MDR1荧光素酶报告基因平台,发现通过激动PXR或CAR来发挥对下游靶基因产生诱导效应的化学成分已经成为新药研发以及临床药学研究的重要手段之一。
联苯双酯(bifendate),是合成五味子素的中间体,是我国研制的降酶药物,常用于肝病的治疗。临床研究发现该药物可以通过稳定肝细胞膜,加强肝细胞损伤的修复,改善肝组织的病理损害。同时联苯双酯作为一种重要的辅助药物,常与环孢素A联合使用,目的是降低环孢素A长期服用带来的肝毒性。临床观察发现,联苯双酯与环孢素A的合用,确实能够降低长期服用环孢素A伴随的肝脏损害,患者体内的环孢素A的血药浓度也出现明显的下降。
基于以上研究背景,本课题旨在查明联苯双酯对CYP3A4以及药物转运体P—糖蛋白在人体产生的影响以及这种影响对联苯双酯与环孢素A在机体的药物相互作用机制探讨的参考价值。通过双荧光素报告基因在转录调控水平探讨联苯双酯对CYP3A4以及P—糖蛋白的影响;通过严格设计的临床实验,探讨在不同CYP3A4*18B基因型的健康受试者体内,联苯双酯对环孢素A药代动力学的影响;以他林洛尔、咪哒唑仑为探药,在整体药代动力学水平和药物相互作用层面探讨联苯双酯对CYP3A4以及P—糖蛋白活性的影响,为临床上联苯双酯与环孢素A药物相互作用提供分子水平解释,并为临床联苯双酯与环孢素A的合理应用以及基因导向个体化治疗提供指导。从整体水平,为初步探讨联苯双酯与环孢素A药物相互作用的机制提供线索。
本课题的主要研究结果如下:
1.在共转染PXR表达质粒和相应启动子的双荧光报告基因检测中,联苯双酯显著增加CYP3A4和MDR1的启动子活性;在共转染CAR表达质粒和相应启动子的双荧光报告基因检测中,联苯双酯对CYP3A4和MDR1的启动子活性没有显著影响。
2.在不同CYP3A4*18B基因型个体中,研究联苯双酯对环孢素A药代动力学参数的影响。发现联苯双酯能够显著降低环孢素A血药浓度,并且环孢素A体内药代参数的变化程度在CYP3A4*18B基因型间有显著差异。
3.用他林洛尔作为探药,研究了联苯双酯对人体P—糖蛋白转运体活性的影响,发现联苯双酯降低了他林洛尔的血药浓度,提示联苯双酯在人体内显著的诱导了P—糖蛋白的转运活性。
4.用咪哒唑仑作为探药,研究了不同CYP3A4*18B基因型个体中联苯双酯对CYP3A4活性的影响,发现咪哒唑仑以及1—羟咪哒唑仑血药浓度在应用联苯双酯后显著降低,并且咪哒唑仑与1—羟咪哒唑仑的AUC_((0-24)),AUC_((0-∞))和Cmax的变化程度在CYP3A4*18B不同基因型间有显著差异,在CYP3A4*18B突变型纯合子型中降低程度最显著。
5.对PXR 1207 C＞T突变在中国汉族人群中的分布频率进行筛查,在80个DNA样本中未发现突变的发生。
总之,本项目从基因转录调控,临床整体水平为联苯双酯与环孢素A的临床药物相互作用和反应的个体差异提供了遗传药理学的解释,为临床合理使用联苯双酯和环孢素A、β-受体阻滞药物他林洛尔、咪哒唑仑以及其它相关药物提供了实验依据和理论指导。
Pharmacogenetics studies indicate that activity change of drug-metabolizing enzymes and transporter is the major mechanism for clinical drug-drug interactions,which is also the key point for the process of bio-transformation and transporting.The inherited variation in activities of drug-metabolizing enzymes and transporters results in interindividual difference in drug metabolism,disposition and efficacy. CyA is a calcineurin inhibitor,which is developed for the treatment of many immune-mediated diseases,especially for the prevention of allograft rejection after the solid organ transplantation.Leukocytes, special helper CD4+ lymphocytes are the main therapeutic targets of this drug.It is regarded as a highly effective in preventing acute rejection, whereas also characterized by a narrow therapeutic index and variable pharmacokinetic characteristics.The process of biotransformation and transporting of cyclosporine is especially via CYP3A4 and P-gp,on which much attention have been paid.
The CYP system is consisted of more than 50 isozymes,by which many exogenous agents and drug are metabolized.Expressed both in liver and small intestine,CYP3A subfamily is found to metabolize about 50%-60%drugs,which is the most abundant CYPs.The variations in the oral bioavailability and the systemic clearance of CYP3A substrates may result from the great interindividual differences in their activity.The studies have found that the variation of CYP3A4 activity does result in the cyclosporine related drug-drug interaction.As the major enzyme involved in the metabolism of drugs,the expressing level of CYP3A4 varies up to 40-fold in the human population,which include inducible and constitute levels.CYP3A4~*18B was speculated to be associated with an increase level of CYP3A4 activity,which could increase the metabolism of cyclosporine.
P-gp is the ATP-binding ex-pumper,which is expressed in liver, small intestine,and kidney and encoded by MDR1.The P-gp played an important role in the process of drug absorption,disposition and elimination.The variation of P-gp activity may lead to the inter-individual difference in the concentration of cyclosporine.
Nuclear receptors PXR and CAR have become hotpoints for pharmacological research by involving in transcriptional regulation of several drug-metabolizing enzymes and transpoters mentioned above. Due to the dual key roles played by PXR and CAR ligands medicated in pharmagology efficacy as well as herb-drug interactions,finding significantly induction of PXR or CAR targeted CYP450 enzymes and drug transporters through activating PXR or CAR using PXR or CAR expressed dual luciferase reporter gene platform becomes crutial in drug development and clinical pharmacology research.Bifendateis a synthetic intermediate of schisandrin C,which is widely used for the treatment of chronic hepatitis,by lowering alanine transaminase(ALT) in patients. Following the intake of bifendate in rats,it was observed to improve liver function by increasing the detoxification process,reducing pathological lesion,accelerating the hepatocyte regeneration.Bifendate can also function as a membrane-stabilizing agent to prevent the cell from the impairment.After the treatment of bifendate,the protein metabolism process of the hepatitis patients was improved,with serum albumin level increased and globulin level decreased.In China,the combined therapy of bifendate with CyA on the patients with renal transplant is found to decrease the side effect of hepatotoxicity induced by CyA,which is also accompanied by the decreased concentration of cyslosporine.
Based on above information,our study was aimed to find effects of bifendate on the activity of CYP3A4 and P-gp,and the mechanism of drug-drug interaction between bifendate and cyclosporine.The effects of bifendate on transcription of CYP3A4 and P-g have been explored by dual-luciferase activity dection.In strictly designed clinical experiment, the effect of bifenate on the pharmacokinetic of cyclosporine in relation to CYP3A4~*18B was evaluated.
Using talinolol and midazolam as the substrate drugs,the potential impact of bifendate on CYP3A4 and P-gp have been clarified.Thepresent study may provide molecular mechanism for the bifendate-cyclosporine interaction,theoretic guidance for combination use of bifendate with cyclosporine,and also the explanation for the bifendate-cyclosporine interaction.
The present series of studies have found that:
1.Bifendate(0.1uM) can significantly increase promoter activities of CYP3A4,MDR1 when cotransfected with PXR-expressed plasmid and dual-luciferase reporter plasmid while bifendate can not significantly increase promoter activities of CYP3A4,MDR1 when cotransfected with CAR-expressed plasmid and dual-luciferase reporter plasmid.
2.Bifendate can decrease the cyclosporine concentration in the CYP3A4~*18B gene dependent manner.
3.Bifendate significantly decreases plasma concentrations and oral bioavailability of talinolol in all subjects,indicating that bifendate can significantly induce P-gp activity in human.
4.Bifendate can decrease significantly decrease the plasma concentration of midazolam and 1-OH-midazolam.The variance of AUC(0-24), AUC(0-∞) and Cmax decreased in the CYP3A4~*18B gene dependent manner.
5.Screening the frequency of PXR 1207 C＞T in Chinese healthy subjects, no mutation of 1207 C＞T was found.
The present study has provided explanation for the bifendate-cyclosporine interaction from gene transcription and clinical investigation and offered the experimental and theoretic guidance for combination use of bifendate with cyclosporine,β-receptor antagonist talinolol and midazolam as well as similar drugs.
环孢素A属于钙调磷酸酶抑制剂家族,主要通过特异性抑制淋巴细胞反应和增生发挥抑制免疫排斥的功效。目前临床上,环孢素A广泛的应用于器官移植术后免疫排斥反应的预防与治疗,该药物在疗效发挥的同时,表现出明显的药物代谢动力学个体差异以及狭窄的治疗窗,由于药物相互作用导致的毒副反应也十分常见。目前的研究证实,环孢素A在人体内的代谢、转运以及与之相关的药物相互作用的发生均与CYP3A4以及P糖蛋白的活性密切相关。针对环孢素A在人体内的药代学以及药效学个体差异所开展的研究也多围绕上述两个功能蛋白开展。
细胞色素P450(CYP450)酶系由基因超家族编码的酶蛋白组成,参与各种内源性以及外源性物质的生物转化。其中,CYP3A4是P450家族中的重要成员,主要表达在肝脏与小肠,参与了临床50%以上药物的代谢,是环孢素A在人体内生物转化过程中最重要的功能蛋白。目前的研究认为,药物对CYP3A4活性的影响,是导致环孢素A相关药物相互作用的主要原因之一。CYP3A4作为机体重要功能蛋白的一种,其活性在基础状态下也存在显著的个体差异。CYP3A4*18B是由日本学者发现的具有功能意义的突变位点.最近的研究发现,该位点的突变与环孢素A在机体内的药代动力学的个体差异密切相关。其中,基因型为CYP3A4*18突变型纯合子的受试者体内环孢素A的代谢显著加强。
P—糖蛋白是由多药耐药基因MDR1编码的一种能量依赖型药物外排泵,在肝脏、小肠、肾脏等人体的多种组织中都有分布。对于各种药物在人体的吸收、分布与消除均发挥重要作用。P—糖蛋白活性的高低与环孢素A在机体代谢的个体差异有着直接的联系。
核受体中的孕烷X受体(pregnane X receptor,PXR)核组成性雄烷受体(constitutive androstane receptor,CAR)对多种CYP450代谢酶以及转运体的转录调节发挥重要作用。目前,利用表达PXR或CAR的CYP450酶以及MDR1荧光素酶报告基因平台,发现通过激动PXR或CAR来发挥对下游靶基因产生诱导效应的化学成分已经成为新药研发以及临床药学研究的重要手段之一。
联苯双酯(bifendate),是合成五味子素的中间体,是我国研制的降酶药物,常用于肝病的治疗。临床研究发现该药物可以通过稳定肝细胞膜,加强肝细胞损伤的修复,改善肝组织的病理损害。同时联苯双酯作为一种重要的辅助药物,常与环孢素A联合使用,目的是降低环孢素A长期服用带来的肝毒性。临床观察发现,联苯双酯与环孢素A的合用,确实能够降低长期服用环孢素A伴随的肝脏损害,患者体内的环孢素A的血药浓度也出现明显的下降。
基于以上研究背景,本课题旨在查明联苯双酯对CYP3A4以及药物转运体P—糖蛋白在人体产生的影响以及这种影响对联苯双酯与环孢素A在机体的药物相互作用机制探讨的参考价值。通过双荧光素报告基因在转录调控水平探讨联苯双酯对CYP3A4以及P—糖蛋白的影响;通过严格设计的临床实验,探讨在不同CYP3A4*18B基因型的健康受试者体内,联苯双酯对环孢素A药代动力学的影响;以他林洛尔、咪哒唑仑为探药,在整体药代动力学水平和药物相互作用层面探讨联苯双酯对CYP3A4以及P—糖蛋白活性的影响,为临床上联苯双酯与环孢素A药物相互作用提供分子水平解释,并为临床联苯双酯与环孢素A的合理应用以及基因导向个体化治疗提供指导。从整体水平,为初步探讨联苯双酯与环孢素A药物相互作用的机制提供线索。
本课题的主要研究结果如下:
1.在共转染PXR表达质粒和相应启动子的双荧光报告基因检测中,联苯双酯显著增加CYP3A4和MDR1的启动子活性;在共转染CAR表达质粒和相应启动子的双荧光报告基因检测中,联苯双酯对CYP3A4和MDR1的启动子活性没有显著影响。
2.在不同CYP3A4*18B基因型个体中,研究联苯双酯对环孢素A药代动力学参数的影响。发现联苯双酯能够显著降低环孢素A血药浓度,并且环孢素A体内药代参数的变化程度在CYP3A4*18B基因型间有显著差异。
3.用他林洛尔作为探药,研究了联苯双酯对人体P—糖蛋白转运体活性的影响,发现联苯双酯降低了他林洛尔的血药浓度,提示联苯双酯在人体内显著的诱导了P—糖蛋白的转运活性。
4.用咪哒唑仑作为探药,研究了不同CYP3A4*18B基因型个体中联苯双酯对CYP3A4活性的影响,发现咪哒唑仑以及1—羟咪哒唑仑血药浓度在应用联苯双酯后显著降低,并且咪哒唑仑与1—羟咪哒唑仑的AUC_((0-24)),AUC_((0-∞))和Cmax的变化程度在CYP3A4*18B不同基因型间有显著差异,在CYP3A4*18B突变型纯合子型中降低程度最显著。
5.对PXR 1207 C＞T突变在中国汉族人群中的分布频率进行筛查,在80个DNA样本中未发现突变的发生。
总之,本项目从基因转录调控,临床整体水平为联苯双酯与环孢素A的临床药物相互作用和反应的个体差异提供了遗传药理学的解释,为临床合理使用联苯双酯和环孢素A、β-受体阻滞药物他林洛尔、咪哒唑仑以及其它相关药物提供了实验依据和理论指导。
Pharmacogenetics studies indicate that activity change of drug-metabolizing enzymes and transporter is the major mechanism for clinical drug-drug interactions,which is also the key point for the process of bio-transformation and transporting.The inherited variation in activities of drug-metabolizing enzymes and transporters results in interindividual difference in drug metabolism,disposition and efficacy. CyA is a calcineurin inhibitor,which is developed for the treatment of many immune-mediated diseases,especially for the prevention of allograft rejection after the solid organ transplantation.Leukocytes, special helper CD4+ lymphocytes are the main therapeutic targets of this drug.It is regarded as a highly effective in preventing acute rejection, whereas also characterized by a narrow therapeutic index and variable pharmacokinetic characteristics.The process of biotransformation and transporting of cyclosporine is especially via CYP3A4 and P-gp,on which much attention have been paid.
The CYP system is consisted of more than 50 isozymes,by which many exogenous agents and drug are metabolized.Expressed both in liver and small intestine,CYP3A subfamily is found to metabolize about 50%-60%drugs,which is the most abundant CYPs.The variations in the oral bioavailability and the systemic clearance of CYP3A substrates may result from the great interindividual differences in their activity.The studies have found that the variation of CYP3A4 activity does result in the cyclosporine related drug-drug interaction.As the major enzyme involved in the metabolism of drugs,the expressing level of CYP3A4 varies up to 40-fold in the human population,which include inducible and constitute levels.CYP3A4~*18B was speculated to be associated with an increase level of CYP3A4 activity,which could increase the metabolism of cyclosporine.
P-gp is the ATP-binding ex-pumper,which is expressed in liver, small intestine,and kidney and encoded by MDR1.The P-gp played an important role in the process of drug absorption,disposition and elimination.The variation of P-gp activity may lead to the inter-individual difference in the concentration of cyclosporine.
Nuclear receptors PXR and CAR have become hotpoints for pharmacological research by involving in transcriptional regulation of several drug-metabolizing enzymes and transpoters mentioned above. Due to the dual key roles played by PXR and CAR ligands medicated in pharmagology efficacy as well as herb-drug interactions,finding significantly induction of PXR or CAR targeted CYP450 enzymes and drug transporters through activating PXR or CAR using PXR or CAR expressed dual luciferase reporter gene platform becomes crutial in drug development and clinical pharmacology research.Bifendateis a synthetic intermediate of schisandrin C,which is widely used for the treatment of chronic hepatitis,by lowering alanine transaminase(ALT) in patients. Following the intake of bifendate in rats,it was observed to improve liver function by increasing the detoxification process,reducing pathological lesion,accelerating the hepatocyte regeneration.Bifendate can also function as a membrane-stabilizing agent to prevent the cell from the impairment.After the treatment of bifendate,the protein metabolism process of the hepatitis patients was improved,with serum albumin level increased and globulin level decreased.In China,the combined therapy of bifendate with CyA on the patients with renal transplant is found to decrease the side effect of hepatotoxicity induced by CyA,which is also accompanied by the decreased concentration of cyslosporine.
Based on above information,our study was aimed to find effects of bifendate on the activity of CYP3A4 and P-gp,and the mechanism of drug-drug interaction between bifendate and cyclosporine.The effects of bifendate on transcription of CYP3A4 and P-g have been explored by dual-luciferase activity dection.In strictly designed clinical experiment, the effect of bifenate on the pharmacokinetic of cyclosporine in relation to CYP3A4~*18B was evaluated.
Using talinolol and midazolam as the substrate drugs,the potential impact of bifendate on CYP3A4 and P-gp have been clarified.Thepresent study may provide molecular mechanism for the bifendate-cyclosporine interaction,theoretic guidance for combination use of bifendate with cyclosporine,and also the explanation for the bifendate-cyclosporine interaction.
The present series of studies have found that:
1.Bifendate(0.1uM) can significantly increase promoter activities of CYP3A4,MDR1 when cotransfected with PXR-expressed plasmid and dual-luciferase reporter plasmid while bifendate can not significantly increase promoter activities of CYP3A4,MDR1 when cotransfected with CAR-expressed plasmid and dual-luciferase reporter plasmid.
2.Bifendate can decrease the cyclosporine concentration in the CYP3A4~*18B gene dependent manner.
3.Bifendate significantly decreases plasma concentrations and oral bioavailability of talinolol in all subjects,indicating that bifendate can significantly induce P-gp activity in human.
4.Bifendate can decrease significantly decrease the plasma concentration of midazolam and 1-OH-midazolam.The variance of AUC(0-24), AUC(0-∞) and Cmax decreased in the CYP3A4~*18B gene dependent manner.
5.Screening the frequency of PXR 1207 C＞T in Chinese healthy subjects, no mutation of 1207 C＞T was found.
The present study has provided explanation for the bifendate-cyclosporine interaction from gene transcription and clinical investigation and offered the experimental and theoretic guidance for combination use of bifendate with cyclosporine,β-receptor antagonist talinolol and midazolam as well as similar drugs.
引文
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