丹参对氯沙坦药代动力学影响及其在中药与西药相互作用中的意义
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摘要
中药在我国及其他亚洲国家历史悠久，已经被证明对慢性病具有良好的治疗优势，具有不良反应少、毒性低等特点，在欧美国家逐步受到重视。以往大多数人认为中药来源于天然植物，安全无毒，也不会像化学药一样易发生药物间的相互作用。事实上，中药含有多种生物活性成分，其化学组成与化学合成药物类似，可通过协同或者拮抗作用共同发挥生理调节作用，也存在与多种类型的药物发生相互作用的可能。以往人们多重视化学药物之间的相互作用，最近有关因中药和化学药相互作用而降低疗效和导致毒副反应的报道日益增多，已引起了医药界的广泛关注。
氯沙坦是第一个用于临床的非肽类血管紧张素II受体阻断药，能竞争性拮抗血管紧张素II受体中的ATI亚型引起的血管收缩，达到降低外周阻力治疗高血压的目的。在体内，氯沙坦主要是通过CYP450酶中的CYP3A4及CYP2C9介导转化成其活性代谢物EXP3174，二者都能与ATI受体选择性结合，发挥抗血管紧张素II的药理作用，从而产生降压作用。丹参其主要成分为丹参酮IIA和丹酚酸B，由于丹参具有活血化瘀、降低血液粘滞度、改善血管弹性等作用，临床上常用来配合氯沙坦治疗原发性高血压，以达到活血通脉及降压目的。但是目前对丹参和氯沙坦的研宄主要集中在药效学领域，而对两者相互作用的研宄较少，因此研宄丹参与氯沙坦的相互作用具有一定的临床意义。本研宄拟通过测定大鼠体内单用氯沙坦和联合使用氯沙坦与丹参及氯沙坦与丹参酮IIA，氯沙坦与丹参多酚酸盐后氯沙坦及活性代谢物EXP3174的药代动力学改变情况，明确丹参及其主要成分对氯沙坦和活性代谢物的影响；同时在体外采用RT-PCR和western-blot法测定丹参主要成分（丹酚酸B和丹参酮IIA)对CYP3A4和CYP2C9酶mRNA和蛋白水平表达的影响，在分子水平从CYP450酶活性的角度阐明丹参与氯沙坦之间相互作用的关系。
本文建立了氯沙坦及代谢物EXP3174在大鼠血浆中的定量分析方法，方法学考察均符合要求，血浆中内源性物质不干扰样品峰，含量测定方法简便可靠，适合于生物样品成分的含量测定，并成功用于氯沙坦与丹参片合并用药后药代动力学的相互作用研宄。实验分为一次给药组和长期给药组，其中长期给药组给予丹参片，丹参酮IIA及丹参多酚酸盐14天，再给予氯沙坦。SD大鼠随机分为4组：A组单独灌胃给药氯沙坦片混悬液；B组灌胃给药氯沙坦片和丹参片混悬液；C组灌胃给药氯沙坦片和丹参酮IIA混悬液；D组灌胃给药氯沙坦片和丹参多酚酸盐混悬液，于氯沙坦给药后在不同时间点从大鼠眼眦静脉丛取血，高效液相色谱-质谱法测定大鼠血浆中氯沙坦和代谢物EXP3174的浓度，采集血药浓度-时间数据，计算其主要药代动力学参数，并进行统计学分析。结果显示：一次给药结果表明，氯沙坦和丹参片联用组与氯沙坦单独用药组相比较，药代动力学参数（Tmax, ti/2, AUCo-24, AUCo, Vd and CL)均有显著性差异(p<0.05)，药物联用后能够降低氯沙坦原型药的半衰期清除率及表观分布容积并延长达峰时间，说明在大鼠体内，丹参或其活性成分能够加快氯沙坦代谢，而代谢物EXP3174的药代动力学参数与单用药相比均无显著性差异，说明氯沙坦经过联用后对代谢物的影响并不明显。长期给药组结果表明：药物经过联用后能够降低氯沙坦原型药的达峰浓度、半衰期、清除率及表观分布容积，说明在大鼠体内，丹参或其活性成分能够诱导氯沙坦代谢。代谢物EXP3174的药代动力学参数与单用药相比，半衰期延长，表观分布容积增加表明丹参片对氯沙坦有一定的诱导作用。长期给药结果与单次给药结果相似，表明丹参片能够影响氯沙坦在体内的代谢，且这种影响是一种诱导作用。本文在中西药联合用药的药代动力学研宄的同时，采用Chang Liver细胞为研宄模型，进行中药有效成分对药物代谢酶系统影响的研宄，在细胞水平阐明丹参制剂影响氯沙坦代谢的分子基础。研宄在Chang Liver细胞中分别加入不同浓度的丹参酮IIA (l,10,100nM)和丹酚酸B (1,10,100^M),用PCR和western-blot法测定CYP3A4和CYP2C9的mRNA和蛋白表达的情况。结果显示：丹参酮IIA和丹酚酸B作用于Chang Liver细胞48小时后，能诱导细胞中CYP3A4和CYP2C9的mRNA及蛋白表达，差异具有统计学意义(p<0.05)，且诱导作用呈浓度依赖性。
本课题以传统中药丹参和西药氯沙坦为研宄示范，综合运用药代动力学，分子生物学等多学科手段，将整体分析（中西药联合用药的药代动力学研宄）和分子水平分析（中药有效成分对药物代谢酶系统影响的研宄）相结合，从分子-细胞-整体动物水平，创新构建基于CYP450酶的系统研宄方法，研宄丹参制剂对氯沙坦代谢水平的影响。丹参和氯沙坦联合用药的药代动力学研宄结果发现，丹参制剂（丹参片、丹参酮IIA注射液以及丹参多酚酸盐）能够加快氯沙坦原型药物在大鼠体内的代谢；在进一步的丹参有效成分对药物代谢酶CYP450影响的研宄中证实了丹参制剂影响氯沙坦代谢的分子基础，即丹参制剂可能是通过诱导CYP3A4及CYP2C9酶的活性而影响氯沙坦的代谢。因此，丹参制剂和氯沙坦在临床上联合使用时可能会存在潜在的相互作用，要注意用药方式和用药剂量的调整。
Traditional Chinese medicine(TCM)，which has a long history in China and otherAsian countries, has already been proven to have a certain advantage of chronic diseasetreatment that hardly leads to adverse or toxic effects and gradually taken seriously byNorth America and Europe. In the past times, most people think of TCM derived fromnatural plants, as safe and non-toxic, unlike the chemical drugs vulnerable to druginteractions. In fact, TCM contains a variety of bio-active ingredients, whose chemicalcomposition is similar with commonly used chemical drugs, thus it can play a role inphysiological regulation together through synergistic or antagonistic effects and is alsopossible to interact with any type of drug. Although most people used to paid attention todrug-drug interaction in the past years, recently, increasing number of suggest thatinteractions between TCM and chemical drugs resulted in decreased eiffcacy and toxicity,which has aroused widespread concern in the medical community.
Losartan is the ifrst nonpeptide angiotensin II receptor blocker，which cancompetitively antagonize vasoconstriction resulted from angiotensin II receptor ATIsubtype, reduce peripheral vascular resistance and enable the treatment of hypertension.While losartan can be transformed into its active metabolite EXP3174mediated bycytochrome CYP450enzymes CYP3A4and CYP2C9and both losartan and its metaboliteEXP3174can be speciifcally combined with the AT1receptors, confront pharmacologicaleffects of angiotensin II and play an antihypertensive action. Danshen is an importanttraditional Chinese multiherbal formula composed of Tanshinonel IIA，Salvianolic acid Band so on，which is widely used for the treatment of cardiovascular and cerebrovasculardiseases in China. Danshen was used in conjunction with losartan in treatment ofhypertension, in order to achieve the purpose of promoting blood circulation and bloodpressure, for its effects of blood circulation, reducing blood viscosity, improving bloodvessel elasticity. However, the current research of Danshen and losartan was limited inifeld of pharmacodynamics, and few researches of interaction between Danshen andlosartan were reported. Therefore，studying the interaction of Danshen and losartan hascertain clinical signiifcance. The aim of this study is to (1) compare the pharmacokineticsof losartan and EXP3174after oral administration of single losartan and both losartan andDanshen tablet, losartan and Tanshinonel IIA, losartan and Salvianolic acid B，andinvestigate the inlfuence of Danshen tablet on the pharmacokinetics of losartan and its metabolite EXP3174;(2) detect effects of chemical compositions of Danshen (salvianolicacid B and tanshinone IIA) on the expression of CYP3A4, CYP2C9enzyme mRNA andprotein level by RT-PCR and western-blot method, and investigate the interaction relationbetween Danshen and losartan based on P450activity in cell level.
A simple, rapid and reliable liquid chromatographic-tandem mass spectrometry(LC-MS) method was developed and validated for the quantiifcation of Los and EXP3174in rat plasma, which meets the current FDA criteria for bioanalytical method validation andwas successfully applied to study interactions between Danshen tablet and Los andEXP3174. The experiment was divided into single-term administration group andlong-term administration group. The long-term medication group was treated withDanshen tablets, tanshinone IIB and salvianolic acid salt for14days, and then treated withlosartan.Male Sprague-Dawley rats were randomly assigned to four groups: single losartangroup, losartan and Danshen tablet group, losartan and Tanshinonel IIA group, losartan andSalvianolic acid B group. Plasma concentrations of losartan and EXP3174weredetermined by LC-MS at designated points after drug administration, and mainpharmacokinetic parameters were estimated. The parameters (Cmax，ti/2, CL) of losartan insingle-term administration group (A) were smaller than those of both losartan and group B.The parameters (k，AUC(o-24)，AUMQ0-24))，AUC，AUMC and MRT) of losartan andEXP3174in group A were bigger than that in group B. The difference was signiifcant(p<0.05). The drug combination can reduce losartan prototype drug ti/2, CL and Vd，prolong the Tmax，suggesting that Danshen and its active ingredients can accelerate themetabolism and metabolites of losartan. But the pharmacokinetic parameters of EXP3174compared with the single drug showed no signiifcant difference，so the effects ofmetabolites is not obvious. Long-term administration group results show that: drugsadministrated in combination with losartan can reduce its T1/2，CL and Vd,suggesting thatDanshen and its active ingredients can induce losartan metabolism in rats. Compared withthe pharmacokinetic parameters of combination drug administration with EXP3174，thoseof single adminitration's are different in that half-life is prolonged andthe apparent volumeof distribution is increased,showing that Danshen tablets have induced effect onlosartan.The results of Long-term administration were similar with the single-termadministration results.lt was found that there was signiifcant difference (p<0.05) betweenthe pharmacokinetic parameters of losartan and EXP3174(Tmax，ti/2, AUCo-24，AUCo-①，Vdand CL), which showed that Danshen tablet can induce the metabolism of losartan in vivo. Besides pharmacokinetic study of chinese-chemical combinational medication, this studyalso analyzed the effects of Chinese herbs on drug metabolizing enzyme system by usingChang liver cell as a model to investigate molecular basis of interaction of Danshen andlosartan in cell level. Expressive levels of CYP3A4，CYP2C9mRNA and protein weredetermined in Chang Liver cells treated by Tanshinonel IIA(l,10,100(iM) and Salvianolicacid B (l，10，100jiM) for48hours using RT-PCR and western-blot. Results showed:Tanshinonel IIA and Salvianolic acid B can signiifcantly induce the expression of CYP3A4and CYP2C9mRNA and protein after Chang liver cells were treated for48hours(p<0.05),and the induction effect is concentration dependent.
This study exempliifed traditional Chinese medicine Danshen and chemical medicinelosartan (Los), which not only applied several tools and approaches based onmultidisciplinary including pharmacokinetics and molecular biology, but also combinedanalyses on integrity level (effects of Chinese herbs on drug metabolizing enzyme system)and molecular level (pharmacokinetic study of chinese-chemical medicine) to constructinnovative system research methods based on CYP450enzyme from molecular-cell-wholeanimal level, and predict possible interaction in drug metabolism level. Results ofpharmacokinetic study of Danshen-losartan medicine showed that Danshen preparation(Danshen tablets, tanshinone IIA injection and salvianolate injection) can accelerate drugmetabolism of losartan in rats; further research in effects of Danshen on CYP450enzymeconifrmed molecular basis of Danshen preparation inlfuencing drug metabolism of losartan,that is Danshen preparation may accelerate drug metabolism of losartan by inducingCYP3A4and CYP2C9enzyme activity. Therefore，Danshen combined with losartan inclinical treatment may exhibit potential interactions, and people should pay attention totheir medication and dosage adjustment.
氯沙坦是第一个用于临床的非肽类血管紧张素II受体阻断药，能竞争性拮抗血管紧张素II受体中的ATI亚型引起的血管收缩，达到降低外周阻力治疗高血压的目的。在体内，氯沙坦主要是通过CYP450酶中的CYP3A4及CYP2C9介导转化成其活性代谢物EXP3174，二者都能与ATI受体选择性结合，发挥抗血管紧张素II的药理作用，从而产生降压作用。丹参其主要成分为丹参酮IIA和丹酚酸B，由于丹参具有活血化瘀、降低血液粘滞度、改善血管弹性等作用，临床上常用来配合氯沙坦治疗原发性高血压，以达到活血通脉及降压目的。但是目前对丹参和氯沙坦的研宄主要集中在药效学领域，而对两者相互作用的研宄较少，因此研宄丹参与氯沙坦的相互作用具有一定的临床意义。本研宄拟通过测定大鼠体内单用氯沙坦和联合使用氯沙坦与丹参及氯沙坦与丹参酮IIA，氯沙坦与丹参多酚酸盐后氯沙坦及活性代谢物EXP3174的药代动力学改变情况，明确丹参及其主要成分对氯沙坦和活性代谢物的影响；同时在体外采用RT-PCR和western-blot法测定丹参主要成分（丹酚酸B和丹参酮IIA)对CYP3A4和CYP2C9酶mRNA和蛋白水平表达的影响，在分子水平从CYP450酶活性的角度阐明丹参与氯沙坦之间相互作用的关系。
本文建立了氯沙坦及代谢物EXP3174在大鼠血浆中的定量分析方法，方法学考察均符合要求，血浆中内源性物质不干扰样品峰，含量测定方法简便可靠，适合于生物样品成分的含量测定，并成功用于氯沙坦与丹参片合并用药后药代动力学的相互作用研宄。实验分为一次给药组和长期给药组，其中长期给药组给予丹参片，丹参酮IIA及丹参多酚酸盐14天，再给予氯沙坦。SD大鼠随机分为4组：A组单独灌胃给药氯沙坦片混悬液；B组灌胃给药氯沙坦片和丹参片混悬液；C组灌胃给药氯沙坦片和丹参酮IIA混悬液；D组灌胃给药氯沙坦片和丹参多酚酸盐混悬液，于氯沙坦给药后在不同时间点从大鼠眼眦静脉丛取血，高效液相色谱-质谱法测定大鼠血浆中氯沙坦和代谢物EXP3174的浓度，采集血药浓度-时间数据，计算其主要药代动力学参数，并进行统计学分析。结果显示：一次给药结果表明，氯沙坦和丹参片联用组与氯沙坦单独用药组相比较，药代动力学参数（Tmax, ti/2, AUCo-24, AUCo, Vd and CL)均有显著性差异(p<0.05)，药物联用后能够降低氯沙坦原型药的半衰期清除率及表观分布容积并延长达峰时间，说明在大鼠体内，丹参或其活性成分能够加快氯沙坦代谢，而代谢物EXP3174的药代动力学参数与单用药相比均无显著性差异，说明氯沙坦经过联用后对代谢物的影响并不明显。长期给药组结果表明：药物经过联用后能够降低氯沙坦原型药的达峰浓度、半衰期、清除率及表观分布容积，说明在大鼠体内，丹参或其活性成分能够诱导氯沙坦代谢。代谢物EXP3174的药代动力学参数与单用药相比，半衰期延长，表观分布容积增加表明丹参片对氯沙坦有一定的诱导作用。长期给药结果与单次给药结果相似，表明丹参片能够影响氯沙坦在体内的代谢，且这种影响是一种诱导作用。本文在中西药联合用药的药代动力学研宄的同时，采用Chang Liver细胞为研宄模型，进行中药有效成分对药物代谢酶系统影响的研宄，在细胞水平阐明丹参制剂影响氯沙坦代谢的分子基础。研宄在Chang Liver细胞中分别加入不同浓度的丹参酮IIA (l,10,100nM)和丹酚酸B (1,10,100^M),用PCR和western-blot法测定CYP3A4和CYP2C9的mRNA和蛋白表达的情况。结果显示：丹参酮IIA和丹酚酸B作用于Chang Liver细胞48小时后，能诱导细胞中CYP3A4和CYP2C9的mRNA及蛋白表达，差异具有统计学意义(p<0.05)，且诱导作用呈浓度依赖性。
本课题以传统中药丹参和西药氯沙坦为研宄示范，综合运用药代动力学，分子生物学等多学科手段，将整体分析（中西药联合用药的药代动力学研宄）和分子水平分析（中药有效成分对药物代谢酶系统影响的研宄）相结合，从分子-细胞-整体动物水平，创新构建基于CYP450酶的系统研宄方法，研宄丹参制剂对氯沙坦代谢水平的影响。丹参和氯沙坦联合用药的药代动力学研宄结果发现，丹参制剂（丹参片、丹参酮IIA注射液以及丹参多酚酸盐）能够加快氯沙坦原型药物在大鼠体内的代谢；在进一步的丹参有效成分对药物代谢酶CYP450影响的研宄中证实了丹参制剂影响氯沙坦代谢的分子基础，即丹参制剂可能是通过诱导CYP3A4及CYP2C9酶的活性而影响氯沙坦的代谢。因此，丹参制剂和氯沙坦在临床上联合使用时可能会存在潜在的相互作用，要注意用药方式和用药剂量的调整。
Traditional Chinese medicine(TCM)，which has a long history in China and otherAsian countries, has already been proven to have a certain advantage of chronic diseasetreatment that hardly leads to adverse or toxic effects and gradually taken seriously byNorth America and Europe. In the past times, most people think of TCM derived fromnatural plants, as safe and non-toxic, unlike the chemical drugs vulnerable to druginteractions. In fact, TCM contains a variety of bio-active ingredients, whose chemicalcomposition is similar with commonly used chemical drugs, thus it can play a role inphysiological regulation together through synergistic or antagonistic effects and is alsopossible to interact with any type of drug. Although most people used to paid attention todrug-drug interaction in the past years, recently, increasing number of suggest thatinteractions between TCM and chemical drugs resulted in decreased eiffcacy and toxicity,which has aroused widespread concern in the medical community.
Losartan is the ifrst nonpeptide angiotensin II receptor blocker，which cancompetitively antagonize vasoconstriction resulted from angiotensin II receptor ATIsubtype, reduce peripheral vascular resistance and enable the treatment of hypertension.While losartan can be transformed into its active metabolite EXP3174mediated bycytochrome CYP450enzymes CYP3A4and CYP2C9and both losartan and its metaboliteEXP3174can be speciifcally combined with the AT1receptors, confront pharmacologicaleffects of angiotensin II and play an antihypertensive action. Danshen is an importanttraditional Chinese multiherbal formula composed of Tanshinonel IIA，Salvianolic acid Band so on，which is widely used for the treatment of cardiovascular and cerebrovasculardiseases in China. Danshen was used in conjunction with losartan in treatment ofhypertension, in order to achieve the purpose of promoting blood circulation and bloodpressure, for its effects of blood circulation, reducing blood viscosity, improving bloodvessel elasticity. However, the current research of Danshen and losartan was limited inifeld of pharmacodynamics, and few researches of interaction between Danshen andlosartan were reported. Therefore，studying the interaction of Danshen and losartan hascertain clinical signiifcance. The aim of this study is to (1) compare the pharmacokineticsof losartan and EXP3174after oral administration of single losartan and both losartan andDanshen tablet, losartan and Tanshinonel IIA, losartan and Salvianolic acid B，andinvestigate the inlfuence of Danshen tablet on the pharmacokinetics of losartan and its metabolite EXP3174;(2) detect effects of chemical compositions of Danshen (salvianolicacid B and tanshinone IIA) on the expression of CYP3A4, CYP2C9enzyme mRNA andprotein level by RT-PCR and western-blot method, and investigate the interaction relationbetween Danshen and losartan based on P450activity in cell level.
A simple, rapid and reliable liquid chromatographic-tandem mass spectrometry(LC-MS) method was developed and validated for the quantiifcation of Los and EXP3174in rat plasma, which meets the current FDA criteria for bioanalytical method validation andwas successfully applied to study interactions between Danshen tablet and Los andEXP3174. The experiment was divided into single-term administration group andlong-term administration group. The long-term medication group was treated withDanshen tablets, tanshinone IIB and salvianolic acid salt for14days, and then treated withlosartan.Male Sprague-Dawley rats were randomly assigned to four groups: single losartangroup, losartan and Danshen tablet group, losartan and Tanshinonel IIA group, losartan andSalvianolic acid B group. Plasma concentrations of losartan and EXP3174weredetermined by LC-MS at designated points after drug administration, and mainpharmacokinetic parameters were estimated. The parameters (Cmax，ti/2, CL) of losartan insingle-term administration group (A) were smaller than those of both losartan and group B.The parameters (k，AUC(o-24)，AUMQ0-24))，AUC，AUMC and MRT) of losartan andEXP3174in group A were bigger than that in group B. The difference was signiifcant(p<0.05). The drug combination can reduce losartan prototype drug ti/2, CL and Vd，prolong the Tmax，suggesting that Danshen and its active ingredients can accelerate themetabolism and metabolites of losartan. But the pharmacokinetic parameters of EXP3174compared with the single drug showed no signiifcant difference，so the effects ofmetabolites is not obvious. Long-term administration group results show that: drugsadministrated in combination with losartan can reduce its T1/2，CL and Vd,suggesting thatDanshen and its active ingredients can induce losartan metabolism in rats. Compared withthe pharmacokinetic parameters of combination drug administration with EXP3174，thoseof single adminitration's are different in that half-life is prolonged andthe apparent volumeof distribution is increased,showing that Danshen tablets have induced effect onlosartan.The results of Long-term administration were similar with the single-termadministration results.lt was found that there was signiifcant difference (p<0.05) betweenthe pharmacokinetic parameters of losartan and EXP3174(Tmax，ti/2, AUCo-24，AUCo-①，Vdand CL), which showed that Danshen tablet can induce the metabolism of losartan in vivo. Besides pharmacokinetic study of chinese-chemical combinational medication, this studyalso analyzed the effects of Chinese herbs on drug metabolizing enzyme system by usingChang liver cell as a model to investigate molecular basis of interaction of Danshen andlosartan in cell level. Expressive levels of CYP3A4，CYP2C9mRNA and protein weredetermined in Chang Liver cells treated by Tanshinonel IIA(l,10,100(iM) and Salvianolicacid B (l，10，100jiM) for48hours using RT-PCR and western-blot. Results showed:Tanshinonel IIA and Salvianolic acid B can signiifcantly induce the expression of CYP3A4and CYP2C9mRNA and protein after Chang liver cells were treated for48hours(p<0.05),and the induction effect is concentration dependent.
This study exempliifed traditional Chinese medicine Danshen and chemical medicinelosartan (Los), which not only applied several tools and approaches based onmultidisciplinary including pharmacokinetics and molecular biology, but also combinedanalyses on integrity level (effects of Chinese herbs on drug metabolizing enzyme system)and molecular level (pharmacokinetic study of chinese-chemical medicine) to constructinnovative system research methods based on CYP450enzyme from molecular-cell-wholeanimal level, and predict possible interaction in drug metabolism level. Results ofpharmacokinetic study of Danshen-losartan medicine showed that Danshen preparation(Danshen tablets, tanshinone IIA injection and salvianolate injection) can accelerate drugmetabolism of losartan in rats; further research in effects of Danshen on CYP450enzymeconifrmed molecular basis of Danshen preparation inlfuencing drug metabolism of losartan,that is Danshen preparation may accelerate drug metabolism of losartan by inducingCYP3A4and CYP2C9enzyme activity. Therefore，Danshen combined with losartan inclinical treatment may exhibit potential interactions, and people should pay attention totheir medication and dosage adjustment.
引文
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