阿司匹林单用与合用琥乙红霉素对大鼠肝药酶活性影响的研究
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摘要
细胞色素P450(cytochrom P450,CYP450)是肝微粒体混合功能氧化酶中最重要的一族,包括多种具有不同专属性底物的同工酶,在催化药物生物转化过程中起着重要作用。涉及药物代谢的CYP450酶主要有CYP1、CYP2、CYP3三族,它们在药物体内代谢过程中起着主要作用,在药理学和毒理学研究中具有重要意义。
由于CYP450酶的活性能被许多化合物诱导或抑制,从而引起药物代谢的改变,产生因药物蓄积或药物相互作用而引发的毒性或不良反应,因此在药物的安全性评价中,研究药物单用或合用对CYP450酶活性的影响受到了人们的重视。首先,了解药物对CYP450酶的诱导或抑制能指导临床药物合理应用,根据药物对CYP450酶诱导或抑制作用的强弱,适当地增加或减少用药剂量,避免不良反应的发生和因达不到治疗浓度而导致的治疗失败。其次,从分子生物学方面研究药物对CYP450酶的诱导或抑制还有利于对肿瘤和其它一些疾病的发生、发展机制进一步探讨,了解CYP450酶对特定前致癌物或前毒物的作用,有目的地使用抑制药抑制其活性以减少毒物或致癌物的生成,这对降低肿瘤等疾病的发病率具有重要意义。
目前,我国心脑血管疾病的发病率增长迅速,已成为导致患者死亡的主要原因之一。合理应用药物预防是逆转心脑血管疾病,延缓疾病进展的一个重要措施。阿司匹林(Aspirin,Asp)为非选择性环加氧酶抑制剂,药理实验及临床实践表明,小剂量阿司匹林可以抑制血小板中环加氧酶1(COX-1),减少血栓素A_2(TXA_2)的生成、降低血小板聚集从而预防心脑血管疾病的发病和短暂性缺血发作,是心肌梗死、缺血性脑血管病高危患者一、二级预防中有效的抗血小板药物。研究表明,50岁以上人群每日口服一或两片阿司匹林(25～50 mg)可以使心脑血管事件下降25～33%。随着人口老龄化的日益严重和用药人群的扩大,阿司匹林以其适应证广泛、价格便宜、效价比高的优点,成为老年患者的临床常用药。由于老年人的多药合用非常普遍,随之而来的药物相互作用研究成为人们关注的热点。
通过对医院老年患者临床用药现状的调查分析,发现老年患者应用阿司匹林和其他药物合用的频率较高。由于老年人呼吸道感染较为常见,琥乙红霉素作为常用的抗菌消炎药,经常与阿司匹林合用;另外,阿司匹林是临床常用的解热镇痛抗炎药,患者发烧时也常和抗菌消炎药琥乙红霉素合用。通过处方调查分析,发现阿司匹林和琥乙红霉素合用较常见,故本实验选择药物合用代表性组合(阿司匹林+琥乙红霉素)进行药物相互作用研究,通过动物体内代谢研究阿司匹林单用与合用琥乙红霉素对大鼠肝脏CYP450酶活性的影响,研究分析药物代谢过程中所涉及的CYP450酶,明确药物作用机制,考察阿司匹林和琥乙红霉素是否存在代谢性相互作用,为指导临床合理用药提供科学依据。
1医院老年患者用药现状及合理性分析
随机抽取保健药房2006年12月5～9日一周处方,共计3012张,按老年患者的姓名、性别、年龄等资料和处方信息逐一录入到《临床药物咨询软件》的处方审查系统中,同时评价老年患者临床用药的合理性,发现老年患者存在服药种类多、潜在的不良相互作用发生率较高的情况。医院医务人员应该通过为患者提供药学监护服务,利用处方审查系统提供用药指南,指导患者合理用药,保证患者用药安全。
2阿司匹林对大鼠肝药酶活性及其CYP450酶亚型基因表达的影响
采用紫外分光光度法和荧光分光光度法考察阿司匹林对大鼠肝药酶的作用,以及这种作用是否受动物性别、给药剂量、用药时间等因素的影响;采用逆转录聚合酶链反应(RT-PCR)技术测定阿司匹林对大鼠肝脏CYP450酶的CYP1A1、CYP2E1、CYP3A1基因表达的影响。结果显示不同剂量阿司匹林对大鼠肝药酶含量和活性均表现不同程度的诱导作用,低剂量阿司匹林对CYP450酶活性的诱导作用不明显,高剂量阿司匹林对CYP450酶活性的诱导作用显著;阿司匹林对大鼠肝脏CYP450酶的诱导作用存在性别差异,且其诱导作用强度和给药剂量与给药时间成正比。中、高剂量用药组大鼠肝脏CYP2E1 mRNA表达量与空白组大鼠比较极显著增加(P＜0.01),高剂量用药组大鼠肝脏CYP3A1 mRNA表达量与空白组大鼠比较增加较显著(P＜0.05),而各用药组大鼠肝脏CYP1A1 mRNA表达量无明显变化。
3阿司匹林合用琥乙红霉素对大鼠肝药酶活性及其CYP450酶亚型基因表达的影响
具体实验方法同上,结果显示阿司匹林单用与合用琥乙红霉素对大鼠肝药酶存在不同的影响:琥乙红霉素对大鼠肝脏红霉素N-脱甲基酶(ERD)和7-乙氧基香豆素脱烃酶(EROD)活性均有明显抑制作用,明显强于阿司匹林对这两种酶的诱导作用;而阿司匹林对大鼠肝脏氨基比林N-脱甲基酶(ADM)和谷胱甘肽S-转移酶(GST)活性均有明显诱导作用,明显强于琥乙红霉素对这两种酶的抑制作用。琥乙红霉素组大鼠肝脏CYP450 mRNA表达量均不同程度降低,以CYP3A1 mRNA表达量降低明显(P＜0.05);而阿司匹林组大鼠肝脏CYP450 mRNA表达量均不同程度增加,以CYP2E1 mRNA表达量增加明显(P＜0.05);合用组大鼠肝脏CYP3A1 mRNA表达量与空白组大鼠比较有所降低(P＜0.05),但与红霉素组大鼠比较有所增加;大鼠肝脏CYP2E1 mRNA表达量与空白组大鼠比较有所增加(P＜0.05),但与阿司匹林组大鼠比较有所降低。
Cytochrom P450(CYP450)is most important among mixed function oxidases in liver microsome,containing many isoenzymes of different specifical substrates.CYP450 plays an important role in biotransformation of mang drugs.CYPl,CYP2,CYP3 are main subfamilies involved in many drugs metabolism.CYP450 is very important in pharmacology and toxicology studies.
Because CYP450 activities can be induced or inhibited by many chemicals,causing the change of drugs metabolism,accumulation of drugs and toxicity or adverse reactions,so the study of CYP450 activities and drug interactions becomes focus. First of all,understanding of CYP450 induction and inhibition,we can direct clinical coadministration of drugs reasonably. According to the extent of induction or inhibition,we can change drug doses to prevent from serious side effects or therapeutic failure due to deficient therapeutic concentration.Secondly,from molecular biology view,we can have a further study of developing mechanism of diseases,especially tumor. Through understanding the effect of CYP450 on transformation of precarcinogens and pretoxicity in vivo,we may lower the incidence of tumor by hibition of CYP450 purposefully to reduce toxicology and carcinogens.
Cardio-cerebral vascular disease has become one of fetal factors because of its high incidence. Drug prevention is useful to change bad tendency and delay disease development. Aspirin(Asp)is a non-selective inhibitor of cyclooxygenase. Experimental pharmacology and clinical practice show that low dose Asp can inhibit COX-1 in thrombocyte and can decrease TXA2 and platelet aggregation,then prevent invasion of cardio-cerebral vascular disease and transient ischemic attack. Asp was found effective as an antiplatelet drug in first and second preservation of myocardial infarction,ischemic cerebrovascular disease for high-risk patients. Taking one or two Asp(25～50mg) can reduce 25～33% Cardio-cerebral vascular events. With serious aging of the population and enlarging patients,Asp becomes a common drug for the aged because of its wide indications,low price and high potency ratio. Drug coadministrations are common in the aged. Drug interaction has become the hot spot.
Through clinical drug administrations analysis of the aged, we found Asp had a high frequency interaction with other drugs. Respiratory infections is common for the aged,erythromycin ethylsuccinate as a wide-used antibacterial anti-inflammatory drug, interacts with Asp.Also,Asp as a wide-used antipyretic analgesic drug,interacts with erythromycin ethylsuccinate for fever patients. Coadministration of Asp and erythromycin ethylsuccinate is common in many prescriptions. So the article is to study how Asp(used alone and combined with Erythromycin Ethylsuccinate)effects CYP450 activities, to find out CYP450 isoenzymes involved in metabolism,to identify mechanism of drug action,to find out whether metabolic interaction exist between the two drugs,to forecast drug interactions process. So the study is of great clinical importance in directing clinical rational drug use.
1 Use condition and reasonable analysis of drug use for the aged in hospital
Collecting 3012 prescriptions(2006.12.05～09)of health care pharmacy randomly, copy the informations(names,genders,ages,prescription contents and so on)into clinical drug advisory software and inspect rationality of clinical drug administration of the aged. We found that many muti-drug administrations and high rates of potiential adverse drug interactions exist among the aged. Through offering pharmaceutical care services and making full use of prescription review system to guide correct and safe drug use.
2 Effects of Aspirin on rat hepatic enzymes activities and CYP subtype genes expressions
Use ultraviolet spectrophotometry and fluorospectrophotometry to study rat hepatic enzymes activities by different doses Asp.To investigate whether Asp inhibit or induce rats hepatic enzymes,whether the effects depend on gender,drug dose and use time.Use RT-PCR to identify rat hepatic CYP1A2,CYP2E1,CYP3A1 genes expressions and effects by different doses Asp. Different doses Asp induced rat hepatic enzymes activities,low dose Asp effects weakly,high dose Asp effects notably. Differences exist between male and female rats,and induction strength extends with drug dose and use time. Middle and High dose group rat hepatic CYP2E1 mRNA express much higher than blank group(P< 0.01) ,high dose group rat hepatic CYP3A1 mRNA express higher than blank group (P< 0. 05) ,there is little difference in CYP1A2 mRNA expression.
3 Effects of Asp coadministration with erythromycin ethylsuccinate on rat hepatic enzymes activities and CYP subtype genes expressions
The methods is similar to the second part.Asp(Alone and combined with erythromycin ethylsuccinate)effect rat hepatic enzymes differently: erythromycin ethylsuccinate inhibits rat hepatic ERD and EROD activities more obviously and can offset induction of Asp. Asp induces rat hepatic ADM and GST activities and can offset inhibition of erythromycin ethylsuccinate. Erythromycin ethylsuccinate group rat hepatic CYP mRNA expression degrades and CYP3A1 mRNA degrades obviously(P<0.05) .Asp group rat hepatic CYP mRNA expression raises and with CYP2E1 mRNA raises obviously(P< 0.05) .Combination group rat hepatic CYP3A1 mRNA expression is lower than blank group(P< 0.05),but higher than erythromycin ethylsuccinate group; CYP2E1 mRNA expression is higher than blank group(P<0.05) ,but lower than Asp group.
由于CYP450酶的活性能被许多化合物诱导或抑制,从而引起药物代谢的改变,产生因药物蓄积或药物相互作用而引发的毒性或不良反应,因此在药物的安全性评价中,研究药物单用或合用对CYP450酶活性的影响受到了人们的重视。首先,了解药物对CYP450酶的诱导或抑制能指导临床药物合理应用,根据药物对CYP450酶诱导或抑制作用的强弱,适当地增加或减少用药剂量,避免不良反应的发生和因达不到治疗浓度而导致的治疗失败。其次,从分子生物学方面研究药物对CYP450酶的诱导或抑制还有利于对肿瘤和其它一些疾病的发生、发展机制进一步探讨,了解CYP450酶对特定前致癌物或前毒物的作用,有目的地使用抑制药抑制其活性以减少毒物或致癌物的生成,这对降低肿瘤等疾病的发病率具有重要意义。
目前,我国心脑血管疾病的发病率增长迅速,已成为导致患者死亡的主要原因之一。合理应用药物预防是逆转心脑血管疾病,延缓疾病进展的一个重要措施。阿司匹林(Aspirin,Asp)为非选择性环加氧酶抑制剂,药理实验及临床实践表明,小剂量阿司匹林可以抑制血小板中环加氧酶1(COX-1),减少血栓素A_2(TXA_2)的生成、降低血小板聚集从而预防心脑血管疾病的发病和短暂性缺血发作,是心肌梗死、缺血性脑血管病高危患者一、二级预防中有效的抗血小板药物。研究表明,50岁以上人群每日口服一或两片阿司匹林(25～50 mg)可以使心脑血管事件下降25～33%。随着人口老龄化的日益严重和用药人群的扩大,阿司匹林以其适应证广泛、价格便宜、效价比高的优点,成为老年患者的临床常用药。由于老年人的多药合用非常普遍,随之而来的药物相互作用研究成为人们关注的热点。
通过对医院老年患者临床用药现状的调查分析,发现老年患者应用阿司匹林和其他药物合用的频率较高。由于老年人呼吸道感染较为常见,琥乙红霉素作为常用的抗菌消炎药,经常与阿司匹林合用;另外,阿司匹林是临床常用的解热镇痛抗炎药,患者发烧时也常和抗菌消炎药琥乙红霉素合用。通过处方调查分析,发现阿司匹林和琥乙红霉素合用较常见,故本实验选择药物合用代表性组合(阿司匹林+琥乙红霉素)进行药物相互作用研究,通过动物体内代谢研究阿司匹林单用与合用琥乙红霉素对大鼠肝脏CYP450酶活性的影响,研究分析药物代谢过程中所涉及的CYP450酶,明确药物作用机制,考察阿司匹林和琥乙红霉素是否存在代谢性相互作用,为指导临床合理用药提供科学依据。
1医院老年患者用药现状及合理性分析
随机抽取保健药房2006年12月5～9日一周处方,共计3012张,按老年患者的姓名、性别、年龄等资料和处方信息逐一录入到《临床药物咨询软件》的处方审查系统中,同时评价老年患者临床用药的合理性,发现老年患者存在服药种类多、潜在的不良相互作用发生率较高的情况。医院医务人员应该通过为患者提供药学监护服务,利用处方审查系统提供用药指南,指导患者合理用药,保证患者用药安全。
2阿司匹林对大鼠肝药酶活性及其CYP450酶亚型基因表达的影响
采用紫外分光光度法和荧光分光光度法考察阿司匹林对大鼠肝药酶的作用,以及这种作用是否受动物性别、给药剂量、用药时间等因素的影响;采用逆转录聚合酶链反应(RT-PCR)技术测定阿司匹林对大鼠肝脏CYP450酶的CYP1A1、CYP2E1、CYP3A1基因表达的影响。结果显示不同剂量阿司匹林对大鼠肝药酶含量和活性均表现不同程度的诱导作用,低剂量阿司匹林对CYP450酶活性的诱导作用不明显,高剂量阿司匹林对CYP450酶活性的诱导作用显著;阿司匹林对大鼠肝脏CYP450酶的诱导作用存在性别差异,且其诱导作用强度和给药剂量与给药时间成正比。中、高剂量用药组大鼠肝脏CYP2E1 mRNA表达量与空白组大鼠比较极显著增加(P＜0.01),高剂量用药组大鼠肝脏CYP3A1 mRNA表达量与空白组大鼠比较增加较显著(P＜0.05),而各用药组大鼠肝脏CYP1A1 mRNA表达量无明显变化。
3阿司匹林合用琥乙红霉素对大鼠肝药酶活性及其CYP450酶亚型基因表达的影响
具体实验方法同上,结果显示阿司匹林单用与合用琥乙红霉素对大鼠肝药酶存在不同的影响:琥乙红霉素对大鼠肝脏红霉素N-脱甲基酶(ERD)和7-乙氧基香豆素脱烃酶(EROD)活性均有明显抑制作用,明显强于阿司匹林对这两种酶的诱导作用;而阿司匹林对大鼠肝脏氨基比林N-脱甲基酶(ADM)和谷胱甘肽S-转移酶(GST)活性均有明显诱导作用,明显强于琥乙红霉素对这两种酶的抑制作用。琥乙红霉素组大鼠肝脏CYP450 mRNA表达量均不同程度降低,以CYP3A1 mRNA表达量降低明显(P＜0.05);而阿司匹林组大鼠肝脏CYP450 mRNA表达量均不同程度增加,以CYP2E1 mRNA表达量增加明显(P＜0.05);合用组大鼠肝脏CYP3A1 mRNA表达量与空白组大鼠比较有所降低(P＜0.05),但与红霉素组大鼠比较有所增加;大鼠肝脏CYP2E1 mRNA表达量与空白组大鼠比较有所增加(P＜0.05),但与阿司匹林组大鼠比较有所降低。
Cytochrom P450(CYP450)is most important among mixed function oxidases in liver microsome,containing many isoenzymes of different specifical substrates.CYP450 plays an important role in biotransformation of mang drugs.CYPl,CYP2,CYP3 are main subfamilies involved in many drugs metabolism.CYP450 is very important in pharmacology and toxicology studies.
Because CYP450 activities can be induced or inhibited by many chemicals,causing the change of drugs metabolism,accumulation of drugs and toxicity or adverse reactions,so the study of CYP450 activities and drug interactions becomes focus. First of all,understanding of CYP450 induction and inhibition,we can direct clinical coadministration of drugs reasonably. According to the extent of induction or inhibition,we can change drug doses to prevent from serious side effects or therapeutic failure due to deficient therapeutic concentration.Secondly,from molecular biology view,we can have a further study of developing mechanism of diseases,especially tumor. Through understanding the effect of CYP450 on transformation of precarcinogens and pretoxicity in vivo,we may lower the incidence of tumor by hibition of CYP450 purposefully to reduce toxicology and carcinogens.
Cardio-cerebral vascular disease has become one of fetal factors because of its high incidence. Drug prevention is useful to change bad tendency and delay disease development. Aspirin(Asp)is a non-selective inhibitor of cyclooxygenase. Experimental pharmacology and clinical practice show that low dose Asp can inhibit COX-1 in thrombocyte and can decrease TXA2 and platelet aggregation,then prevent invasion of cardio-cerebral vascular disease and transient ischemic attack. Asp was found effective as an antiplatelet drug in first and second preservation of myocardial infarction,ischemic cerebrovascular disease for high-risk patients. Taking one or two Asp(25～50mg) can reduce 25～33% Cardio-cerebral vascular events. With serious aging of the population and enlarging patients,Asp becomes a common drug for the aged because of its wide indications,low price and high potency ratio. Drug coadministrations are common in the aged. Drug interaction has become the hot spot.
Through clinical drug administrations analysis of the aged, we found Asp had a high frequency interaction with other drugs. Respiratory infections is common for the aged,erythromycin ethylsuccinate as a wide-used antibacterial anti-inflammatory drug, interacts with Asp.Also,Asp as a wide-used antipyretic analgesic drug,interacts with erythromycin ethylsuccinate for fever patients. Coadministration of Asp and erythromycin ethylsuccinate is common in many prescriptions. So the article is to study how Asp(used alone and combined with Erythromycin Ethylsuccinate)effects CYP450 activities, to find out CYP450 isoenzymes involved in metabolism,to identify mechanism of drug action,to find out whether metabolic interaction exist between the two drugs,to forecast drug interactions process. So the study is of great clinical importance in directing clinical rational drug use.
1 Use condition and reasonable analysis of drug use for the aged in hospital
Collecting 3012 prescriptions(2006.12.05～09)of health care pharmacy randomly, copy the informations(names,genders,ages,prescription contents and so on)into clinical drug advisory software and inspect rationality of clinical drug administration of the aged. We found that many muti-drug administrations and high rates of potiential adverse drug interactions exist among the aged. Through offering pharmaceutical care services and making full use of prescription review system to guide correct and safe drug use.
2 Effects of Aspirin on rat hepatic enzymes activities and CYP subtype genes expressions
Use ultraviolet spectrophotometry and fluorospectrophotometry to study rat hepatic enzymes activities by different doses Asp.To investigate whether Asp inhibit or induce rats hepatic enzymes,whether the effects depend on gender,drug dose and use time.Use RT-PCR to identify rat hepatic CYP1A2,CYP2E1,CYP3A1 genes expressions and effects by different doses Asp. Different doses Asp induced rat hepatic enzymes activities,low dose Asp effects weakly,high dose Asp effects notably. Differences exist between male and female rats,and induction strength extends with drug dose and use time. Middle and High dose group rat hepatic CYP2E1 mRNA express much higher than blank group(P< 0.01) ,high dose group rat hepatic CYP3A1 mRNA express higher than blank group (P< 0. 05) ,there is little difference in CYP1A2 mRNA expression.
3 Effects of Asp coadministration with erythromycin ethylsuccinate on rat hepatic enzymes activities and CYP subtype genes expressions
The methods is similar to the second part.Asp(Alone and combined with erythromycin ethylsuccinate)effect rat hepatic enzymes differently: erythromycin ethylsuccinate inhibits rat hepatic ERD and EROD activities more obviously and can offset induction of Asp. Asp induces rat hepatic ADM and GST activities and can offset inhibition of erythromycin ethylsuccinate. Erythromycin ethylsuccinate group rat hepatic CYP mRNA expression degrades and CYP3A1 mRNA degrades obviously(P<0.05) .Asp group rat hepatic CYP mRNA expression raises and with CYP2E1 mRNA raises obviously(P< 0.05) .Combination group rat hepatic CYP3A1 mRNA expression is lower than blank group(P< 0.05),but higher than erythromycin ethylsuccinate group; CYP2E1 mRNA expression is higher than blank group(P<0.05) ,but lower than Asp group.
引文
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