氟喹诺酮类对猪和鸡肝微粒体CYP1A2活性影响研究
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摘要
肝微粒体细胞色素P450酶系(Cytochrome P450,CYP450)是生物体内主要负责外源性物质和内源性物质Ⅰ相代谢的超家族酶系统。药物在被CYP450代谢的过程中可能对CYP450活性产生诱导与抑制作用,从而影响自身或其它药物的代谢。当多种药物联合使用时,这种酶活性改变可能会导致另外一种或几种药物代谢改变,出现药物失效甚至毒副作用,这也是临床上药物代谢性相互作用(Drug-druginteraction,DDI)产生的重要原因之一。为避免药物相互作用带来更大的损失,FDA先后于1997和2006年公布了相应的指导性文件以加强对药物的安全性评价与监测。兽医领域加强和完善兽药对CYP450活性影响的研究,对指导兽医临床合理和安全用药、预防和避免潜在的药物相互作用具有重要意义。
氟喹诺酮类药物(Fluoroquinolones,FQs)是第三代含氟的新型喹诺酮类(Quinolones)药物,具有抗菌谱广、杀菌能力强、吸收分布广、不良反应小等显著特点,在兽医临床上得到了广泛的应用。CYP1A2是CYP450代谢酶系中的重要成员之一,参与临床上5%-10%常规药物的代谢。实验动物包括大鼠、小鼠、狗及人的研究表明FQs对肝微粒体CYP1A2亚型的活性存在抑制作用,这也是其与许多药物发生相互作用的重要原因。但目前尚无该类药物对食品动物猪和鸡肝微粒体CYP1A2活性影响研究的报道。由于种属差异的存在,单纯依靠种属外推来预测FQs对食品动物肝微粒体CYP1A2活性的影响存在很大的不足,因此有必要直接以食品动物为靶动物进行相关研究。本试验采用体外探针药物法研究了当前兽医临床常用的8种FQs包括环丙沙星、诺氟沙星、氧氟沙星、洛美沙星、恩诺沙星、达氟沙星、二氟沙星、沙拉沙星对猪和鸡肝微粒体CYP1A2活性的影响,为其在兽医临床更合理和安全的使用提供科学依据。本试验主要包括以下三个方面的内容:
1.肝微粒体CYP1A2活性检测体外探针药物法(HPLC-UV法)的建立及优化
本试验以非那西丁O-去乙基反应(Phenacetin O-deethylation,POD)为探针检测肝微粒体CYP1A2亚型的活性。建立肝微粒体中非那西丁及扑热息痛同时检测的HPLC-UV法(梯度洗脱)。结果表明,猪和鸡肝微粒体中内源性物质均不干扰扑热息痛和非那西丁的测定,且猪和鸡肝微粒体中扑热息痛与非那西丁响应值与浓度均具有良好的线性关系,精密度和准确度均达到要求。
差速离心法制备肝微粒体后测定CYP450差示光谱,考查探针药物非那西丁在微粒体中的代谢以检测肝微粒体活性,并建立肝微粒体体外孵育系统。结果表明,猪和鸡肝微粒体在450nm处有最大吸收,非那西丁在微粒体中能代谢生成扑热息痛,说明肝微粒体存在活性可用于代谢研究。
采用共同孵育的方法考查6种常用的人源性CYP450抑制剂对猪和鸡肝微粒体非那西丁代谢的影响。结果表明,α-萘黄酮、花椒霉素和4-甲基吡酮均对猪肝微粒体中非那西丁O-脱乙基反应有抑制作用,其他抑制剂无显著影响,α-萘黄酮抑制作用最强,其K_i值为16.8μmol/L,是基于可逆抑制的非竞争性抑制作用:α-萘黄酮、磺胺苯吡唑、4-甲基吡酮、喹尼丁和花椒霉素均对鸡肝微粒体非那西丁O-脱乙基反应有抑制作用,其他抑制剂无显著影响,α-萘黄酮抑制作用最强,其K_i值为19.8μmol/L,是基于可逆抑制的非竞争性抑制作用。
2.8种FQs对猪肝微粒体CYP1A2活性影响研究
FQs(500μmol/L)在猪肝微粒体孵育系统中预先反应不同时间(0min、10min、20min、30min)后继续反应15min,绘制FQs的预反应时间-依赖性抑制图(TDI)确定抑制作用的类型;不同浓度的FQs(0、500、1000μmol/L)与非那西丁(1.25、2.5、5、10、20、40μmol/L)在猪肝微粒体孵育体系中反应15min,通过Linweaver-Burk法作图研究抑制作用产生的机制。结果表明8种FQs均对猪肝微粒体CYP1A2活性有较弱的抑制作用。环丙沙星、二氟沙星、沙拉沙星和洛美沙星产生的是基于不可逆抑制类型的非竞争性抑制作用,达氟沙星、氧氟沙星、恩诺沙星和诺氟沙星产生的是基于可逆抑制类型的非竞争性抑制作用。
3.8种FQs对鸡肝微粒体CYP1A2活性影响研究
FQs(500μmol/L)在鸡肝微粒体孵育系统中预先反应不同时间(0min、10min、20min、30min)后继续反应20min,绘制FQs的预反应时间-依赖性抑制图(TDI)确定抑制作用的类型:不同浓度的FQs(0、500、1000μmol/L)与非那西丁(2.5、5、10、20、40、80μmol/L)在鸡肝微粒体孵育体系中反应20min,通过Linweaver-Burk法作图研究抑制作用产生的机制。结果表明8种FQs均对鸡肝微粒体CYP1A2活性有较弱的抑制作用。环丙沙星产生的是基于不可逆抑制类型的非竞争性抑制作用,沙拉沙星产生的是基于不可逆抑制类型的竞争性抑制作用,达氟沙星和洛美沙星产生的是基于可逆抑制类型的非竞争性抑制作用,诺氟沙星、二氟沙星、氧氟沙星、恩诺沙星产生的是基于可逆抑制类型的竞争性抑制作用。
本试验所建立的体外探针法可用于猪和鸡肝微粒体CYP1A2活性的检测。该方法具有取材方便、检测结果稳定、重复性好,特异性好、精确度高等优点。本试验所考查的FQs的K_i均远大于其在正常使用下的血药浓度C_(max)(K_i/C_(max)＞10),因此兽医临床上合理使用这8种FQs时均不会因其对CYP1A2活性的抑制作用而引发DDI。但是,由于不可逆抑制作用存在蓄积效应,因此临床上要尽量避免和减少环丙沙星、沙拉沙星、洛美沙星和二氟沙星的连续给药。本试验第一次得到了FQs对猪和鸡肝微粒体CYP1A2活性抑制的相关酶动力学参数,这对临床更加合理使用FQs、避免药物相互作用具有重要的指导意义。
Cytochromes P450(CYP450) is a superfamily of enzymes that take responsibility for phaseⅠmetabolism of foreign compounds and endogenous compounds in liver.The process of metabolising may be alterant as the activity of enzyme induced or inhibited by drugs,which may change the pharmacological and toxicological effect of drug itself or other drugs and even lead to fatal side-effec including drug-drug interaction(DDI) in clinics.In 1997 and 2006,testing of DDI has been the subject of FDA guidance documents,so as to avoid the risk of DDI in the development of new drugs and in clinics. It is of great importance to reinforce the reseach about induction and inhibition of CYP450,which is also important to advisable use of drugs and prevention of DDI in veterinary clinics.
Fluoroquinolones(FQs),the third new type quinolones antibacterial agents with fluorin,are extensively used in veterinary clinics as wide antibacterial spectrum,strong antibacterial activity,efficient absorption and low side-effect.CYP1A2 is one of the major CYP450 isoforms that take part in nearly 5%-10%of drug metabolism at clinics.It is reported that some FQs have inhibitory effect on CYP1A2 activities in human and other laboratory animal like rats and dogs,which leading to some side effect at clinical states. But there are no relative reports in pig and chicken.It is essential to complete the research of CYP450 inhibition of FQs on food-producing animals as the species-difference is significant.This study was designed for integral investigation about the potential inhibitory effect of eight FQs including ciprofloxacin(CFX),norfloxacin(NFX),ofloxacin (OFX),lomefloxacin(LFX),enrofloxacin(EFX),danofloxacin(DFX),difloxacin(DIFX), sarafloxacin(SFX) on CYP1A2 activities in pig and chicken.The information of inhibitory magnitude and mechanism were determined with probe method in vitro,which was consisted of three parts as follows.
1.Probe method(HPLC-UV) in vitro for CYP1A2 in mierosomes
Phenacetin O-deethylation(POD) was used as the classical probe for measuring CYP1A2 activity in liver microsomes.Phenacetin(PHE) and acetaminophen(ACE) were determined together by HPLC-UV using the gradient.The results showed that there was no interference for ACE and PHE in pig and chicken hepatic microsomes,and a good linear correlation for ACE and PHE in each calibration range,while the accuracy and precision were both good.
Fresh liver was surgically obtained from pig and chicken then hepatic microsomes were prepared by differential centrifugation to establish the incubation syetem.The enzymeatic activities of microsomes were investigated by the carbon monoxide(CO) differential spectrum and the metabolism of PHE.The spectrum had peak at 450nm and PHE could be metabolized to ACE in microsomes,indicating that these microsomes could be used for drug metabolism.Then the microsomal incubation system were established for PHE in pig and chicken,respectively.
The incubation system had been examined through enzyme inhibition with chmical inhibitors for 6 main CYP450 isoforms by coinstantaneous incubation.In pig, alpha-naphthoflavone,xanthotoxin and 4-methylpyrazone had inhibitory effect on CYP1A2 activity,while other inhibitors had no siginificant inhibition.Alpha-naphthoflavone inhibited CYP1A2 activity in non-competitive manner,the K_i value was 16.8μmol/L.In chicken,alpha-naphthoflavone,sulfaphenazole,4-methylpyrazone, xanthotoxin and quinidine had inhibitory effect on CYP1A2 activity,while other inhibitors had no siginificant inhibition.Alpha-naphthoflavone inhibited CYP1A2 activity in noncompetitive manner,the K_i value was 19.8μmol/L.
2.Inhibitory effect of eight FQs on hepatic CYP1A2 isoenzyme activities in pig microsomes
FQs(at the concentration of 500μmol/L) were pre-incubated for a certain time(0min, 10min,20min,30min) before the incubation(15 min) with phenacetin(at the concentration of 10μmol/L) in PLMs,then TDI figure was drawed to show the manner of inhibition;FQs(at the concentrations of 0,500,1000μmol/L) and PHE(at the concentrations of 1.25,2.5,5,10,20,40μmol/L) were incubated together for 15 min,then Lineweaver-Burk plots were estabolished to study the mechanism of inhibition.All the FQs had weak inhibitory effect on CYP1A2 activity in pig.DFX,OFX,EFX and NFX had noncompetitive inhibition in reversible manner,while CFX,DIFX,SFX and LFX had noncompetitive inhibition in irreversible manner.
3.Inhibitory effect of eight FQs on hepatic CYP1A2 isoenzyme activities in chicken microsomes
FQs(at the concentration of 500μmol/L) were pre-incubated for a certain time(0min, 10min,20min,30min) before the incubation(20 min) with PHE(at the concentration of 10μmol/L) in CLMs,then TDI figure was drawed to show the manner of inhibition;FQs (at the concentrations of 0,500,1000μmol/L) and PHE(at the concentrations of 1.25,2.5, 5,10,20,40μmol/L) were incubated together for 20 min,then Lineweaver-Burk plots were estabolished to study the mechanism of inhibition.All the FQs had weak inhibitory effect on CYP1A2 activity in chicken too.CFX had noncompetitive inhibition in irreversible manner,SFX had competitive inhibition in irreversible manner,DFX and LFX had noncompetitive inhibition that in reversible manner,NFX,DIFX,OFX and EFX had competitive inhibition in reversible manner.
The sigle probe assay in vitro for CYP1A2 in pig and chicken liver microsomes have many merits including better stability,repeatability,specificity and fidelity,which could be used for determing CYP1A2 activity.All the eight FQs examined are safe while advisable using,as the inhibitory effect are too weak to cause DDI at clinics(K_i /C_(max)＞10).But it is better to avoid the perseverative use of CFX,SFX,LFX and DIFX as the irrevisible inhibitory effect could be accumulated.The enzymatic parameters of FQs on CYP1A2 activities in pig and chicken were obtained,which could be useful for optimal use of FQs at veterinary clinics.
氟喹诺酮类药物(Fluoroquinolones,FQs)是第三代含氟的新型喹诺酮类(Quinolones)药物,具有抗菌谱广、杀菌能力强、吸收分布广、不良反应小等显著特点,在兽医临床上得到了广泛的应用。CYP1A2是CYP450代谢酶系中的重要成员之一,参与临床上5%-10%常规药物的代谢。实验动物包括大鼠、小鼠、狗及人的研究表明FQs对肝微粒体CYP1A2亚型的活性存在抑制作用,这也是其与许多药物发生相互作用的重要原因。但目前尚无该类药物对食品动物猪和鸡肝微粒体CYP1A2活性影响研究的报道。由于种属差异的存在,单纯依靠种属外推来预测FQs对食品动物肝微粒体CYP1A2活性的影响存在很大的不足,因此有必要直接以食品动物为靶动物进行相关研究。本试验采用体外探针药物法研究了当前兽医临床常用的8种FQs包括环丙沙星、诺氟沙星、氧氟沙星、洛美沙星、恩诺沙星、达氟沙星、二氟沙星、沙拉沙星对猪和鸡肝微粒体CYP1A2活性的影响,为其在兽医临床更合理和安全的使用提供科学依据。本试验主要包括以下三个方面的内容:
1.肝微粒体CYP1A2活性检测体外探针药物法(HPLC-UV法)的建立及优化
本试验以非那西丁O-去乙基反应(Phenacetin O-deethylation,POD)为探针检测肝微粒体CYP1A2亚型的活性。建立肝微粒体中非那西丁及扑热息痛同时检测的HPLC-UV法(梯度洗脱)。结果表明,猪和鸡肝微粒体中内源性物质均不干扰扑热息痛和非那西丁的测定,且猪和鸡肝微粒体中扑热息痛与非那西丁响应值与浓度均具有良好的线性关系,精密度和准确度均达到要求。
差速离心法制备肝微粒体后测定CYP450差示光谱,考查探针药物非那西丁在微粒体中的代谢以检测肝微粒体活性,并建立肝微粒体体外孵育系统。结果表明,猪和鸡肝微粒体在450nm处有最大吸收,非那西丁在微粒体中能代谢生成扑热息痛,说明肝微粒体存在活性可用于代谢研究。
采用共同孵育的方法考查6种常用的人源性CYP450抑制剂对猪和鸡肝微粒体非那西丁代谢的影响。结果表明,α-萘黄酮、花椒霉素和4-甲基吡酮均对猪肝微粒体中非那西丁O-脱乙基反应有抑制作用,其他抑制剂无显著影响,α-萘黄酮抑制作用最强,其K_i值为16.8μmol/L,是基于可逆抑制的非竞争性抑制作用:α-萘黄酮、磺胺苯吡唑、4-甲基吡酮、喹尼丁和花椒霉素均对鸡肝微粒体非那西丁O-脱乙基反应有抑制作用,其他抑制剂无显著影响,α-萘黄酮抑制作用最强,其K_i值为19.8μmol/L,是基于可逆抑制的非竞争性抑制作用。
2.8种FQs对猪肝微粒体CYP1A2活性影响研究
FQs(500μmol/L)在猪肝微粒体孵育系统中预先反应不同时间(0min、10min、20min、30min)后继续反应15min,绘制FQs的预反应时间-依赖性抑制图(TDI)确定抑制作用的类型;不同浓度的FQs(0、500、1000μmol/L)与非那西丁(1.25、2.5、5、10、20、40μmol/L)在猪肝微粒体孵育体系中反应15min,通过Linweaver-Burk法作图研究抑制作用产生的机制。结果表明8种FQs均对猪肝微粒体CYP1A2活性有较弱的抑制作用。环丙沙星、二氟沙星、沙拉沙星和洛美沙星产生的是基于不可逆抑制类型的非竞争性抑制作用,达氟沙星、氧氟沙星、恩诺沙星和诺氟沙星产生的是基于可逆抑制类型的非竞争性抑制作用。
3.8种FQs对鸡肝微粒体CYP1A2活性影响研究
FQs(500μmol/L)在鸡肝微粒体孵育系统中预先反应不同时间(0min、10min、20min、30min)后继续反应20min,绘制FQs的预反应时间-依赖性抑制图(TDI)确定抑制作用的类型:不同浓度的FQs(0、500、1000μmol/L)与非那西丁(2.5、5、10、20、40、80μmol/L)在鸡肝微粒体孵育体系中反应20min,通过Linweaver-Burk法作图研究抑制作用产生的机制。结果表明8种FQs均对鸡肝微粒体CYP1A2活性有较弱的抑制作用。环丙沙星产生的是基于不可逆抑制类型的非竞争性抑制作用,沙拉沙星产生的是基于不可逆抑制类型的竞争性抑制作用,达氟沙星和洛美沙星产生的是基于可逆抑制类型的非竞争性抑制作用,诺氟沙星、二氟沙星、氧氟沙星、恩诺沙星产生的是基于可逆抑制类型的竞争性抑制作用。
本试验所建立的体外探针法可用于猪和鸡肝微粒体CYP1A2活性的检测。该方法具有取材方便、检测结果稳定、重复性好,特异性好、精确度高等优点。本试验所考查的FQs的K_i均远大于其在正常使用下的血药浓度C_(max)(K_i/C_(max)＞10),因此兽医临床上合理使用这8种FQs时均不会因其对CYP1A2活性的抑制作用而引发DDI。但是,由于不可逆抑制作用存在蓄积效应,因此临床上要尽量避免和减少环丙沙星、沙拉沙星、洛美沙星和二氟沙星的连续给药。本试验第一次得到了FQs对猪和鸡肝微粒体CYP1A2活性抑制的相关酶动力学参数,这对临床更加合理使用FQs、避免药物相互作用具有重要的指导意义。
Cytochromes P450(CYP450) is a superfamily of enzymes that take responsibility for phaseⅠmetabolism of foreign compounds and endogenous compounds in liver.The process of metabolising may be alterant as the activity of enzyme induced or inhibited by drugs,which may change the pharmacological and toxicological effect of drug itself or other drugs and even lead to fatal side-effec including drug-drug interaction(DDI) in clinics.In 1997 and 2006,testing of DDI has been the subject of FDA guidance documents,so as to avoid the risk of DDI in the development of new drugs and in clinics. It is of great importance to reinforce the reseach about induction and inhibition of CYP450,which is also important to advisable use of drugs and prevention of DDI in veterinary clinics.
Fluoroquinolones(FQs),the third new type quinolones antibacterial agents with fluorin,are extensively used in veterinary clinics as wide antibacterial spectrum,strong antibacterial activity,efficient absorption and low side-effect.CYP1A2 is one of the major CYP450 isoforms that take part in nearly 5%-10%of drug metabolism at clinics.It is reported that some FQs have inhibitory effect on CYP1A2 activities in human and other laboratory animal like rats and dogs,which leading to some side effect at clinical states. But there are no relative reports in pig and chicken.It is essential to complete the research of CYP450 inhibition of FQs on food-producing animals as the species-difference is significant.This study was designed for integral investigation about the potential inhibitory effect of eight FQs including ciprofloxacin(CFX),norfloxacin(NFX),ofloxacin (OFX),lomefloxacin(LFX),enrofloxacin(EFX),danofloxacin(DFX),difloxacin(DIFX), sarafloxacin(SFX) on CYP1A2 activities in pig and chicken.The information of inhibitory magnitude and mechanism were determined with probe method in vitro,which was consisted of three parts as follows.
1.Probe method(HPLC-UV) in vitro for CYP1A2 in mierosomes
Phenacetin O-deethylation(POD) was used as the classical probe for measuring CYP1A2 activity in liver microsomes.Phenacetin(PHE) and acetaminophen(ACE) were determined together by HPLC-UV using the gradient.The results showed that there was no interference for ACE and PHE in pig and chicken hepatic microsomes,and a good linear correlation for ACE and PHE in each calibration range,while the accuracy and precision were both good.
Fresh liver was surgically obtained from pig and chicken then hepatic microsomes were prepared by differential centrifugation to establish the incubation syetem.The enzymeatic activities of microsomes were investigated by the carbon monoxide(CO) differential spectrum and the metabolism of PHE.The spectrum had peak at 450nm and PHE could be metabolized to ACE in microsomes,indicating that these microsomes could be used for drug metabolism.Then the microsomal incubation system were established for PHE in pig and chicken,respectively.
The incubation system had been examined through enzyme inhibition with chmical inhibitors for 6 main CYP450 isoforms by coinstantaneous incubation.In pig, alpha-naphthoflavone,xanthotoxin and 4-methylpyrazone had inhibitory effect on CYP1A2 activity,while other inhibitors had no siginificant inhibition.Alpha-naphthoflavone inhibited CYP1A2 activity in non-competitive manner,the K_i value was 16.8μmol/L.In chicken,alpha-naphthoflavone,sulfaphenazole,4-methylpyrazone, xanthotoxin and quinidine had inhibitory effect on CYP1A2 activity,while other inhibitors had no siginificant inhibition.Alpha-naphthoflavone inhibited CYP1A2 activity in noncompetitive manner,the K_i value was 19.8μmol/L.
2.Inhibitory effect of eight FQs on hepatic CYP1A2 isoenzyme activities in pig microsomes
FQs(at the concentration of 500μmol/L) were pre-incubated for a certain time(0min, 10min,20min,30min) before the incubation(15 min) with phenacetin(at the concentration of 10μmol/L) in PLMs,then TDI figure was drawed to show the manner of inhibition;FQs(at the concentrations of 0,500,1000μmol/L) and PHE(at the concentrations of 1.25,2.5,5,10,20,40μmol/L) were incubated together for 15 min,then Lineweaver-Burk plots were estabolished to study the mechanism of inhibition.All the FQs had weak inhibitory effect on CYP1A2 activity in pig.DFX,OFX,EFX and NFX had noncompetitive inhibition in reversible manner,while CFX,DIFX,SFX and LFX had noncompetitive inhibition in irreversible manner.
3.Inhibitory effect of eight FQs on hepatic CYP1A2 isoenzyme activities in chicken microsomes
FQs(at the concentration of 500μmol/L) were pre-incubated for a certain time(0min, 10min,20min,30min) before the incubation(20 min) with PHE(at the concentration of 10μmol/L) in CLMs,then TDI figure was drawed to show the manner of inhibition;FQs (at the concentrations of 0,500,1000μmol/L) and PHE(at the concentrations of 1.25,2.5, 5,10,20,40μmol/L) were incubated together for 20 min,then Lineweaver-Burk plots were estabolished to study the mechanism of inhibition.All the FQs had weak inhibitory effect on CYP1A2 activity in chicken too.CFX had noncompetitive inhibition in irreversible manner,SFX had competitive inhibition in irreversible manner,DFX and LFX had noncompetitive inhibition that in reversible manner,NFX,DIFX,OFX and EFX had competitive inhibition in reversible manner.
The sigle probe assay in vitro for CYP1A2 in pig and chicken liver microsomes have many merits including better stability,repeatability,specificity and fidelity,which could be used for determing CYP1A2 activity.All the eight FQs examined are safe while advisable using,as the inhibitory effect are too weak to cause DDI at clinics(K_i /C_(max)＞10).But it is better to avoid the perseverative use of CFX,SFX,LFX and DIFX as the irrevisible inhibitory effect could be accumulated.The enzymatic parameters of FQs on CYP1A2 activities in pig and chicken were obtained,which could be useful for optimal use of FQs at veterinary clinics.
引文
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