无肝状态下大鼠芬太尼的代谢及小肠组织CYP3A1酶表达变化的研究
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摘要
研究背景
芬太尼是临床肝移植手术中最常用的强效麻醉性镇痛药,主要在肝脏代谢,代谢产物与约10%的原形药由肾脏排出。肝移植手术中在无肝期失去肝脏的主要代谢作用后,芬太尼的代谢会受到怎样的影响,影响其代谢的因素是什麽,通过哪种途径产生影响,目前对这方面的报道较少。细胞色素P450(cytochromeP450)属于血红素蛋白基因超家族,编码一系列代谢酶系统,参与各类不同结构亲脂性化合物的生物转化,增强代谢物水溶性,利于其排出体外,从而降低外源化合物对机体靶器官的毒性效应。在CYP超家族中,涉及芬太尼代谢的CYP3A亚家族成员为CYP3A4(人),其在大鼠体内的同源蛋白为CYP3A1/2。肠内CYP450酶主要为CYP3A4亚族,分布于上皮细胞。已有的研究证实,肠内CYP3A与肝脏中的CYP3A酶cDNA序列一样。将芬太尼代谢酶表达活性的改变与药代动力学特征相结合有助于深入了解无肝期芬太尼代谢的特征,为临床用药提供参考。
目的
本实验以大鼠为动物模型,小肠为研究对象,解剖分离并阻断肝门,模拟临床肝移植无肝期,观察入肝血流阻断前后芬太尼血药浓度的变化,计算其代谢的相关参数;观察细胞色素P450酶系中芬太尼代谢相关CYP3A1酶活性的变化,并通过RT-PCR和Western-blot技术观察CYP3A1基因、蛋白的表达和变化,为初步探讨芬太尼无肝状态下的代谢途径及作用机制提供依据。
材料和方法
实验分为三部分:
1.无肝状态下大鼠芬太尼血药浓度的变化。采用芬太尼标准品(1 g/ml,纯度99.9 %),通过高效液相色谱—质谱联用(LC-MS/MS)分析仪,制备大鼠芬太尼血药浓度标准曲线,建立微量血样检测芬太尼浓度的实验方法。SPF级雄性大鼠25只,5只用于建立芬太尼标准曲线,其余随机分为对照组(A1)和处理组(A2)(每组10只),大鼠麻醉后,处理组阻断入肝血流,夹闭肝门,两组均由右侧颈深静脉置入24#静脉留置针,用于采血;右股静脉切开,置入24#静脉留置针,A1组直接,A2组于夹闭肝门后静脉注射芬太尼(20μg/kg),分别于注药后1、2、3、5、10、15、20、30、45、60、70、90 min等时间点由颈静脉各采血0.5 ml,同时回输等量乳酸林格液。采用LC-MS/MS方法检测各时相点血药浓度,并应用DAS2.0药代动力学软件测算芬太尼的消除半衰期、清除率、表观分布容积和药-时曲线下面积。
2.芬太尼代谢相关CYP3A1酶活性的研究。30只SPF级雄性大鼠随机分为3组,每组10只,B1为对照组,B2为阻断肝门30 min组,B3为阻断肝门60 min组。大鼠麻醉后,B1组直接,B2、B3组分别在相应时间点纵行开腹,截取距胃幽门4 cm处小肠组织,采用免疫荧光比色法定量检测各实验组酶活性的变化。
3.阻断肝门后芬太尼代谢相关CYP3A1在小肠表达和变化的研究。将大鼠分为三组,正常对照(C1)组、阻断肝门30min(C2)组、阻断肝门60min(C3)组,n=10,大鼠小肠组织采用逆转录聚合酶链式反应(RT-PCR)检测各实验组CYP3A1 mRNA的表达;免疫印迹(Western-blot)技术检测各实验组CYP3A1蛋白的表达。
结果
1.在选定的色谱条件下,测得芬太尼色谱图被测物与内标物两者峰形良好,分离完全,无杂质峰干扰,芬太尼及内标的保留时间良好;芬太尼标准曲线方程为y = 0.0156 x + 0.0072(r = 0. 9997),大鼠体内芬太尼最低检测浓度为0.5 ng/ml,检测方法精密优良。
2.在阻断肝门的情况下,单次剂量注射芬太尼后其血药浓度仍呈下降趋势,但下降速度减缓,尽管消除半衰期明显延长,药-时曲线下面积明显增大,但清除率、表观分布容积无显著变化。
3.阻断肝门后小肠组织CYP3A1酶活性比阻断肝门前增强,差异具有统计学意义(P < 0.05),阻断肝门30 min和阻断肝门60 min相比较差异无统计学意义(P > 0. 05)。
4. CYP3A1酶mRNA和蛋白的表达水平阻断肝门后30 min和60 min均高于阻断肝门前,具有统计学差异(P < 0.05),阻断肝门30 min和阻断肝门60 min相比较差异无统计学意义(P > 0. 05)。
结论
1.本实验建立的微量血样检测芬太尼血药浓度的方法特异性强,日间日内变异小,线性范围广,简便准确。
2.无肝期芬太尼的代谢特点为血药浓度下降缓慢,Vd、CL无明显改变,T1/2β延长,AUC明显增大。
3.肝脏是芬太尼代谢的主要器官,无肝状态下芬太尼可能存在有其他代谢途径。
4.小肠组织芬太尼代谢相关CYP3A1酶活性在无肝期明显增强,可能为无肝状态下,芬太尼肝外代谢的机制之一。
5.小肠组织芬太尼代谢相关CYP3A1酶mRNA的表达和蛋白的表达在无肝期均增强,可能是使CYP3A1酶含量增多,促进芬太尼在小肠代谢的分子机制之一。同时酶含量增多,活性增强可能是芬太尼无肝状态代谢特点形成的原因之一。
Background:
Fentanyl is an intravenous narcotic analgesics with high efficiency and most commonly used in liver transplantation. As an opiate receptor agonist, it takes effect very rapidly, lasts a very short time in blood, does not release histamine, and has little effect on cardiovascular function. It is metabolized mainly in the liver, and its metabolites and about 10%original drug are discharged by the kidneys. In liver transplant operation, there is no liver metabolism during anhepatic phase. How is fentanyl metabolized? And what will influence this proscess?These questions remain unclear. Cytochrome P450 (CYP), a member of the hemoprotein gene superfamily, encodes a series of metabolic enzymes, participates biological transformation of lipophilc compounds in various structures, and enhances the water-solubility of the metabolic products which will be prone to be discharged so as to reduce the toxicity of these exogenous compounds. The liver has the highest contents of CYP3A1 among other tissues and organs. Its expression is modulated in an immediate, tissue-specific and environment-related manner. In the anhepatic phase of liver transplantation, internal milieu changes vigorously, and the levels of some hormones may affect extrahepatic expression of CYP3A1, thus influencing extrahepatic metabolism of fentanyl. In small intestine, CYP3A4 is the main form and distributed in the epithelial cells.
Objective:
In this study, fentanyl metabolism in anhepatic rats was studied, and the changes in CYP3A1 enzymatic activity, gene expression and protein expression in small intestine before and after the anhepatic phase were also investigated. This study was aimed to preliminarily elucidate how the anhepatic state influences the CYP3A1 expression and what fentanyl metabolism is in the anhepatic phase.
Materials and Methods:
This study is composed of three parts:
1. Fentanyl plasma cocentration changes in the anhepatic rats.
Five SPF male SD rats were used to plot the standard curve of blood fentanyl concentration, and another 20 were equally divided into control and treatment group (anhepatic group). After all rats were etherized, a 24# vein detaining-pin was inserted into their right deep cervical vein to collect blood sample, and another detaining-pin was set to the right femoral vein to add fentanyl. In treatment group, fentanyl (20μg/kg) was infused after hepatic hilum blocking, and blood sample (0.5 ml) was colleted in 1, 2, 3, 5, 10, 15, 30, 45, 60, 70 and 90 min after the infusion. Rats of control group did not receive hepatic hilum blocking. The fentanyl concentration was measured with LC-MS/MS and analyzed with DAS2.0 Pharmacokinetics Program. The standard curve of rat blood fentanyl concentration was plotted by high performance liquid chromatograph-mass spectrogram using standard fentanyl (1μg/ml, purity 99.9%), and the method for measuring fentanyl concentration with small volume of blood sample was established.
2. Extrahepatic expression of fentanyl metabolism related CYP3A1 in the anhepatic phase.
Totally 30 SPF male SD rats were equally and randomly divided into the control groups (group B1, as before the anhepatic phase), rats with hepatic portal blocking for 30 min (group B2, as 30 min anhepatic phase), and rats with 60 min blocking (groupB3, as 60 min anhepatic phase). All rats were treated as done in part 1 for drug injection and infusion. The intestinal specimen 4 cm from the stomachus pyloricus was taken out, and the activity of CYP3A1 in the specimens was detected by colorimetry.
3. Extrahepatic expression of CYP3A1 gene and protein in the anhepatic phase. The rats were randomly divided into (n=10 in each group): control group (group C1, before the anhepatic phase), group C2 (30 min anhepatic phase) and group C3 (60 min anhepatic phase).After etherization, small intestine were harvested, and CYP3A1 mRNA and protein expression was detected by RT-PCR and Western blotting respectively.
Results:
1. Under the selected chromatographic conditions, the samples and the internal standard of fentanyl showed satisfactory and completely-separated peaks and had no interference of impurity peak, and maintained in a sound time period. The standard curve equation of fentanyl was y = 0.0156 x+0.0072 (r=0.9997, P<0.05). The minimal detectable concentration of fentanyl was 0.5 ng/ml, indicating the detection method is highly precise.
2. Before and after the anhepatic phase, single dose of fentanyl did not change significantly with CL and Vd (P>0.05), AUC and T1/2βchanged obviously.(P<0.05).
3. CYP3A1 activity in small intestine was significantly higher after 30 min or 60 min anhepatic phase than before the anhepatic phase (P<0.05), but no significant difference was seen between 30 min and 60 min of the anhepatic phase (P>0.05).
4. The expression of CYP3A1 gene and protein in rat small intestine was significantly higher after 30 min or 60 min anhepatic phase than before the anhepatic phase (P<0.05), but there is no significant difference between 30 min and 60 min anhepatic phase(P>0.05).
Conclusions:
1. The method of measuring blood fentanyl concentration in small volume of blood sample is specific, simple and accurate, with little time variation and wide linear range. It can be used as a conventional assay measuring blood fentanyl concentration.
2. Melabolism of fentanyl during the anhepatic phase is characterized with no significantly changed CL and Vd, prolonged T1/2βand obviously increased AUC.
3. Liver is the main organ to metabolize fentanyl, but there maybe other ways for fentanyl metabolization.
4. CYP3A1 activity in small intestine is significantly higher in the anhepatic phase, indicating it maybe one of the mechanism for frntanyl metabolized in small intestine.
5. The expression of CYP3A1 gene and protein in rat small intestine is significantly higher in the anhepatic phase, which maybe one of the mechanism about the elevated enzymic activity and extrahepatic metabolism of fentanyl. Simultaneously, it maybe one of the reasons that generate the metabolic characters in the rat small intestine about fentanyl.
芬太尼是临床肝移植手术中最常用的强效麻醉性镇痛药,主要在肝脏代谢,代谢产物与约10%的原形药由肾脏排出。肝移植手术中在无肝期失去肝脏的主要代谢作用后,芬太尼的代谢会受到怎样的影响,影响其代谢的因素是什麽,通过哪种途径产生影响,目前对这方面的报道较少。细胞色素P450(cytochromeP450)属于血红素蛋白基因超家族,编码一系列代谢酶系统,参与各类不同结构亲脂性化合物的生物转化,增强代谢物水溶性,利于其排出体外,从而降低外源化合物对机体靶器官的毒性效应。在CYP超家族中,涉及芬太尼代谢的CYP3A亚家族成员为CYP3A4(人),其在大鼠体内的同源蛋白为CYP3A1/2。肠内CYP450酶主要为CYP3A4亚族,分布于上皮细胞。已有的研究证实,肠内CYP3A与肝脏中的CYP3A酶cDNA序列一样。将芬太尼代谢酶表达活性的改变与药代动力学特征相结合有助于深入了解无肝期芬太尼代谢的特征,为临床用药提供参考。
目的
本实验以大鼠为动物模型,小肠为研究对象,解剖分离并阻断肝门,模拟临床肝移植无肝期,观察入肝血流阻断前后芬太尼血药浓度的变化,计算其代谢的相关参数;观察细胞色素P450酶系中芬太尼代谢相关CYP3A1酶活性的变化,并通过RT-PCR和Western-blot技术观察CYP3A1基因、蛋白的表达和变化,为初步探讨芬太尼无肝状态下的代谢途径及作用机制提供依据。
材料和方法
实验分为三部分:
1.无肝状态下大鼠芬太尼血药浓度的变化。采用芬太尼标准品(1 g/ml,纯度99.9 %),通过高效液相色谱—质谱联用(LC-MS/MS)分析仪,制备大鼠芬太尼血药浓度标准曲线,建立微量血样检测芬太尼浓度的实验方法。SPF级雄性大鼠25只,5只用于建立芬太尼标准曲线,其余随机分为对照组(A1)和处理组(A2)(每组10只),大鼠麻醉后,处理组阻断入肝血流,夹闭肝门,两组均由右侧颈深静脉置入24#静脉留置针,用于采血;右股静脉切开,置入24#静脉留置针,A1组直接,A2组于夹闭肝门后静脉注射芬太尼(20μg/kg),分别于注药后1、2、3、5、10、15、20、30、45、60、70、90 min等时间点由颈静脉各采血0.5 ml,同时回输等量乳酸林格液。采用LC-MS/MS方法检测各时相点血药浓度,并应用DAS2.0药代动力学软件测算芬太尼的消除半衰期、清除率、表观分布容积和药-时曲线下面积。
2.芬太尼代谢相关CYP3A1酶活性的研究。30只SPF级雄性大鼠随机分为3组,每组10只,B1为对照组,B2为阻断肝门30 min组,B3为阻断肝门60 min组。大鼠麻醉后,B1组直接,B2、B3组分别在相应时间点纵行开腹,截取距胃幽门4 cm处小肠组织,采用免疫荧光比色法定量检测各实验组酶活性的变化。
3.阻断肝门后芬太尼代谢相关CYP3A1在小肠表达和变化的研究。将大鼠分为三组,正常对照(C1)组、阻断肝门30min(C2)组、阻断肝门60min(C3)组,n=10,大鼠小肠组织采用逆转录聚合酶链式反应(RT-PCR)检测各实验组CYP3A1 mRNA的表达;免疫印迹(Western-blot)技术检测各实验组CYP3A1蛋白的表达。
结果
1.在选定的色谱条件下,测得芬太尼色谱图被测物与内标物两者峰形良好,分离完全,无杂质峰干扰,芬太尼及内标的保留时间良好;芬太尼标准曲线方程为y = 0.0156 x + 0.0072(r = 0. 9997),大鼠体内芬太尼最低检测浓度为0.5 ng/ml,检测方法精密优良。
2.在阻断肝门的情况下,单次剂量注射芬太尼后其血药浓度仍呈下降趋势,但下降速度减缓,尽管消除半衰期明显延长,药-时曲线下面积明显增大,但清除率、表观分布容积无显著变化。
3.阻断肝门后小肠组织CYP3A1酶活性比阻断肝门前增强,差异具有统计学意义(P < 0.05),阻断肝门30 min和阻断肝门60 min相比较差异无统计学意义(P > 0. 05)。
4. CYP3A1酶mRNA和蛋白的表达水平阻断肝门后30 min和60 min均高于阻断肝门前,具有统计学差异(P < 0.05),阻断肝门30 min和阻断肝门60 min相比较差异无统计学意义(P > 0. 05)。
结论
1.本实验建立的微量血样检测芬太尼血药浓度的方法特异性强,日间日内变异小,线性范围广,简便准确。
2.无肝期芬太尼的代谢特点为血药浓度下降缓慢,Vd、CL无明显改变,T1/2β延长,AUC明显增大。
3.肝脏是芬太尼代谢的主要器官,无肝状态下芬太尼可能存在有其他代谢途径。
4.小肠组织芬太尼代谢相关CYP3A1酶活性在无肝期明显增强,可能为无肝状态下,芬太尼肝外代谢的机制之一。
5.小肠组织芬太尼代谢相关CYP3A1酶mRNA的表达和蛋白的表达在无肝期均增强,可能是使CYP3A1酶含量增多,促进芬太尼在小肠代谢的分子机制之一。同时酶含量增多,活性增强可能是芬太尼无肝状态代谢特点形成的原因之一。
Background:
Fentanyl is an intravenous narcotic analgesics with high efficiency and most commonly used in liver transplantation. As an opiate receptor agonist, it takes effect very rapidly, lasts a very short time in blood, does not release histamine, and has little effect on cardiovascular function. It is metabolized mainly in the liver, and its metabolites and about 10%original drug are discharged by the kidneys. In liver transplant operation, there is no liver metabolism during anhepatic phase. How is fentanyl metabolized? And what will influence this proscess?These questions remain unclear. Cytochrome P450 (CYP), a member of the hemoprotein gene superfamily, encodes a series of metabolic enzymes, participates biological transformation of lipophilc compounds in various structures, and enhances the water-solubility of the metabolic products which will be prone to be discharged so as to reduce the toxicity of these exogenous compounds. The liver has the highest contents of CYP3A1 among other tissues and organs. Its expression is modulated in an immediate, tissue-specific and environment-related manner. In the anhepatic phase of liver transplantation, internal milieu changes vigorously, and the levels of some hormones may affect extrahepatic expression of CYP3A1, thus influencing extrahepatic metabolism of fentanyl. In small intestine, CYP3A4 is the main form and distributed in the epithelial cells.
Objective:
In this study, fentanyl metabolism in anhepatic rats was studied, and the changes in CYP3A1 enzymatic activity, gene expression and protein expression in small intestine before and after the anhepatic phase were also investigated. This study was aimed to preliminarily elucidate how the anhepatic state influences the CYP3A1 expression and what fentanyl metabolism is in the anhepatic phase.
Materials and Methods:
This study is composed of three parts:
1. Fentanyl plasma cocentration changes in the anhepatic rats.
Five SPF male SD rats were used to plot the standard curve of blood fentanyl concentration, and another 20 were equally divided into control and treatment group (anhepatic group). After all rats were etherized, a 24# vein detaining-pin was inserted into their right deep cervical vein to collect blood sample, and another detaining-pin was set to the right femoral vein to add fentanyl. In treatment group, fentanyl (20μg/kg) was infused after hepatic hilum blocking, and blood sample (0.5 ml) was colleted in 1, 2, 3, 5, 10, 15, 30, 45, 60, 70 and 90 min after the infusion. Rats of control group did not receive hepatic hilum blocking. The fentanyl concentration was measured with LC-MS/MS and analyzed with DAS2.0 Pharmacokinetics Program. The standard curve of rat blood fentanyl concentration was plotted by high performance liquid chromatograph-mass spectrogram using standard fentanyl (1μg/ml, purity 99.9%), and the method for measuring fentanyl concentration with small volume of blood sample was established.
2. Extrahepatic expression of fentanyl metabolism related CYP3A1 in the anhepatic phase.
Totally 30 SPF male SD rats were equally and randomly divided into the control groups (group B1, as before the anhepatic phase), rats with hepatic portal blocking for 30 min (group B2, as 30 min anhepatic phase), and rats with 60 min blocking (groupB3, as 60 min anhepatic phase). All rats were treated as done in part 1 for drug injection and infusion. The intestinal specimen 4 cm from the stomachus pyloricus was taken out, and the activity of CYP3A1 in the specimens was detected by colorimetry.
3. Extrahepatic expression of CYP3A1 gene and protein in the anhepatic phase. The rats were randomly divided into (n=10 in each group): control group (group C1, before the anhepatic phase), group C2 (30 min anhepatic phase) and group C3 (60 min anhepatic phase).After etherization, small intestine were harvested, and CYP3A1 mRNA and protein expression was detected by RT-PCR and Western blotting respectively.
Results:
1. Under the selected chromatographic conditions, the samples and the internal standard of fentanyl showed satisfactory and completely-separated peaks and had no interference of impurity peak, and maintained in a sound time period. The standard curve equation of fentanyl was y = 0.0156 x+0.0072 (r=0.9997, P<0.05). The minimal detectable concentration of fentanyl was 0.5 ng/ml, indicating the detection method is highly precise.
2. Before and after the anhepatic phase, single dose of fentanyl did not change significantly with CL and Vd (P>0.05), AUC and T1/2βchanged obviously.(P<0.05).
3. CYP3A1 activity in small intestine was significantly higher after 30 min or 60 min anhepatic phase than before the anhepatic phase (P<0.05), but no significant difference was seen between 30 min and 60 min of the anhepatic phase (P>0.05).
4. The expression of CYP3A1 gene and protein in rat small intestine was significantly higher after 30 min or 60 min anhepatic phase than before the anhepatic phase (P<0.05), but there is no significant difference between 30 min and 60 min anhepatic phase(P>0.05).
Conclusions:
1. The method of measuring blood fentanyl concentration in small volume of blood sample is specific, simple and accurate, with little time variation and wide linear range. It can be used as a conventional assay measuring blood fentanyl concentration.
2. Melabolism of fentanyl during the anhepatic phase is characterized with no significantly changed CL and Vd, prolonged T1/2βand obviously increased AUC.
3. Liver is the main organ to metabolize fentanyl, but there maybe other ways for fentanyl metabolization.
4. CYP3A1 activity in small intestine is significantly higher in the anhepatic phase, indicating it maybe one of the mechanism for frntanyl metabolized in small intestine.
5. The expression of CYP3A1 gene and protein in rat small intestine is significantly higher in the anhepatic phase, which maybe one of the mechanism about the elevated enzymic activity and extrahepatic metabolism of fentanyl. Simultaneously, it maybe one of the reasons that generate the metabolic characters in the rat small intestine about fentanyl.
引文
1. Kharasch E D ,Whittington D , Hoffer C. Influence of hepatic and intestinal cytochrome P450 3A activity on the acute disposition and effects of oralt ransmucosal fentanyl cit rate. [J] Anesthesiology,2004,101(3) :729-737.
2.周宏灏,主编.遗传药理学.[M]第二版.北京:科学出版社,2001 : 53 - 235.
3. Huynh NH, Tyrefors N, Ekman L, Johansson M. Determination of fentanyl in human plasma and fentanyl and norfentanyl in human urine using LC–MS/MS.[J] Journal of Pharmaceutical and Biomedical Analysis, 2005, 37 (5):1095-1100
4. Lahoz A. Determination of major human cytochrome P450s activities in 96-well plates using liquid chromatography tandem mass spectrometry. [J] Toxicology in Vitro, 2007, 21 (7): 1247–1252
5.宋振玉,刘耕陶.当代药理学.[M]北京:中国协和医科大学联合出版社, 1994
6. Krishna D R, Klotz U. Extrahepatic metabolism of drug in humans.[J] Clin Pharmacokinet, 1994, 26:1442-1601
7.王羽,药物的肝外代谢. [J]药学进展, 2004 , 28(7): 289-293
8. Morgan A R et al. Metablism and Disposition. [J] Drug, 1998, 26(12):1232-1236
9. Jin Mj. Contributions of intestinal P-glycoprotein and CYP3A to oral bioavailability of cyclosporin A in mice treated with or without dexamethas. [J] International journal opharmaceutics,2006 , 309 (12):81-86
10. Xu DX, Wei W, Sun MF, et al. Kupffer cells and ROS partially mediate LPS-induced down-regulation of nuclear receptor Pregnane X receptor and its target gene CYP3A in mouse liver. [J] Free Radic BiolMed, 2004, 37 (1): 10 - 22.
11. Kanokwan, Jarukamjorn. Modified expression of cytochrome P450 mRNAs by growth hormone in mouse liver. [J] Toxicology, 2006, 219 (13):97–105
12. Staudinger JL, Goodwin B, Jones SA, et al. The nuclear receptor PXR is a lithocholoc acid sensor that protects against liver toxicity.[J] Proc Natl Acad Sci USA, 2001, 98 (7): 3369 - 3374.
13. Prajakti A, kothare, Cheryl L, et al. Intestinal metabolism: the role of enzyme localization in phenol metabolism kinetics.[J] Drug Metab Dispos, 2002, 30 (5):586-594.
14.顾健腾,陶国才,鲁开智,等.大鼠肾脏异丙酚代谢相关ugt1a6基因在无肝期表达变化的研究. [J]第三军医大学学报, 2005,27 (16) : 1697– 1699)
15. Zhao Lin, Li Lin-Fang, Wu Meng-Chao An in vivo rat model for assessment of extrahepatic metabolism. [J] Journal of Pharmacological and Toxicological Methods, 2001, (45): 181– 185
16.张红,方熠,王淑君等,高效液相色谱法测定人血浆中芬太尼的浓度.[J]同济大学学报(医学版),2005,26(1):49-50
17.李正翔,赵晴,董伟林,高效液相色谱法测定人血浆中芬太尼浓度.[J]中国医院药学杂志,2004,24(10):607-609
18. Habib Bagheri, Ali Es-haghi, Faezeh Khalilian et al. Determination of fentanyl in human plasma by head-space solid-phasemicroextr action and gas chromatography–mass spectrometry.[J] Journal of Pharmaceutical and Biomedical Analysis 2007,43 (12) :1763–1768
19. Hak Soo Choia, Ho-Chul Shinb, Gilson Khanga, et al.Quantitative analysis of fentanyl in rat plasma by gas chromatography with nitrogen–phosphorus detection.[J] Journal of Chromatography 2001, 765 (B): 63–69
20. J.Guitton, M.Desage, S.Alamercery, et al. Gas chromatographic-mass spectrometry and gas chromatographic-Fourier transform infrared spectroscopy assay for the simultaneous identification of fentanyl metabolites.[J] Joural of chromatography 1997,59 (b):59-70
21.张利萍,张现化,张蕾等,LC/MS/MS联用技术测定全血中瑞芬太尼浓度.[J]中国新药杂志,2006,15(2):137-139
22. Yi-Wei Chang, Hsien-Tsung Yao, Yu-Sheng Chao,et al Rapid and sensitive determination of fentanyl in dog plasma by on-line solid-phase extraction integrated with a hydrophilic column coupled to tandem mass spectrometry.[J] Journal of Chromatography B, 2007 (857) 195–201
23. Joel G.Hardman, Alfred Goodman The Pharmacological Basis of Therapetics第10版:465-467
24. Shafer, S. L, Varvel, J.R., Aziz, N. et al.Pharmacokinetics of fentanyl administred by computercontrolled infusion pump.[J] Anesthesiology, 1990,73:1091-1102
25.庄心良,曾因明,陈伯銮.现代麻醉学.人民卫生出版社.2003,第三版
26.顾健腾,陶国才,易斌等.持续恒速输注异丙酚在大鼠无肝期前后血药浓度变化的研究.[J]第三军医大学学报, 2005,27 (17) : 1766–1769
27.张蕾,张利萍,张现化等,原位肝移植患者静注瑞芬太尼的药代动力学.[J]中国临床药理学杂志,2007,23(6):437-441
28. Rendic S. Summary of information on human CYP enzymes: human P450 metabolism data. [J] D rug Metab Rev, 2002; 34: 83– 448
29. NebertDW, AdesnikM, CoonMJ, et al. The P450 gene superfamily: recommended nomenclature. [J] DNA, 1987; 6: 1 - 11.
30.徐启明,李文硕,临床麻醉学.人民卫生出版社.2000,第一版
31. De Waziers I, Cugnenc P H, Yang C S et al. Cytochorome P450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues.[J] Pharm.Exp.Ther.1990, 258:387-391
32.姚欣,钱元恕.肝外药物代谢酶的研究进展.[J]国外医学药学分册,2003 , 30(2) :97-101
33.冷星夫,邱星辉.细胞色素P450酶系的结构、功能与应用前景,科学出版社.2001,56-69
34. Zhang Y, Benet LZ. The gut as a drug absorption: combined role of cytochrome P450 3A and p-glycoprotein. [J] Clin Pharmacokinet, 2001, 40 (3):159 - 168.
35. Shin-Pei Yang, Theresa Medling, Gregory M. Raner. Cytochrome P450 expression and activities in rat, rabbit and bovine tongue.[J] Comparative Biochemistry and Physiology Part C, 2003,136 (22) 297–308.
36. Paine MF, Schmiedlin2Ren P, Watkins PB. Cytochrome P450 1A1 expression in human small bowel: interindividual variation and inhibition by ketoconazole. [J] Drug Metab Dispos , 1999 , 27(3) :360– 364
37. Yoshihiro Konno, Masashi Sekimoto, Kiyomitsu Nemoto.et al Sex difference in induction of hepatic CYP2B and CYP3A subfamily enzymes by nicardipine and nifedipine in rats.[J] Toxicology and Applied Pharmacology, 2004,6(19): 20– 28
38. Tsutomu Shimada, Koichi,okogawa, Masaaki Nomur.Site-dependent contributions of P-glycoprotein and CYP3A to cyclosporin A absorption, and effect of dexamethasone in small intestine of mice.[J] Biochemical Pharmacology,2006,72 (8):1042-1050
39.张宾,周晰.黄芪对糖尿病大鼠CYP450酶系活性的影响.[J]中药药理与临床.2007,23(4):36-38
40.李平,程建峰,陈东鸿等.地塞米松、苯巴比妥钠和利多卡因对昆明种小鼠肝P450 3A酶的影响.[J]第四军医大学学报,2001,22(1):26-28
41.余爱荣,辛华雯,吴笑春等.环孢素A与盐酸小檗碱合用对大鼠肝脏和小肠药物代谢酶的影响.[J]中国医院药学杂志,2005, 25 (2):104-106
42.曹安民,施畅,刘雁等.酮康唑对大鼠肝脏CYP450酶系的影响.[J]中国新药杂志.2007,16(4):285-287
43. Amaia Irizar, Costas Ioannides, Marked inhibition of hepatic cytochrome P450 activity in cholesterol-induced atherosclerosis in rabbits. [J] Toxicology 1998 (126) :179–193
44. Liddle C, Goodwin B J, George J et al. Separate and interactive regulation of cytochrome P4503A4 by triiodothyronine dexamethasone and groth hormone in cultured hepatocytes.[J] Clin. Endocrinol. Metab.1998,83 (2):2411-2416
45. Peterson TC, Hodgson P, Fernandez2Salguero P , Neumeister M, Gonalez FJ . Hepatic fibrosis and cytochrome P450: experimental models of fibrosis compared to AHR knockoutmice. [J] Hepatol Res, 2000, 17 (2):112 - 125.
46. Wang H, Chen M, Liao ZX. Changes of liver xenobiotic-metabolizing function at the different status of hepatic injury.[J] Chin Pharmacol Bull (中国药理学报) , 2004 , 20(7) :772 - 775.
47. Wang XD , Ar′Rajab A , Andersson R , Soltesz V , Wang W, Svensson M, et al . The influ- -ence of surgically induced acute liver failure on the intestine in the rat.[J] Scand J Gastroenterol, 1993, 28 (1):31 - 40.
48. Kasravi FB , Wang L , Wang XD , Molin G, Bengmark S ,Jeppsson B.Bacterial translocation in acute liver injury induced by D-galactosamine.[J] Hepatology, 1996, 23 (1) :97 - 103.
49.胡小玲,汪晖,吴基良等.肝纤维化状态下小肠药物代谢功能的改变.[J]中国药理学与毒理学杂志,2004,18(5):379-384
50. Peter A.Chr. Hoen, Jan N. M. Commandeur. Selective Induction of Cytochrome P450 3A1 by Dexamethasone in Cultured Rat Hepatocytes.[J] Biochemical Pharmacology, 2000, ,60 (2):1059-1518
51. Tsutomu Sakuma, Yusuke Endo, Misae Mashino.et al Regulation of the expression of two female-predominant CYP3AmRNAs in mouse liver by sex and growthhormones.[J] Archives of Biochemistry and Biophysics,2002,404(2):234-242
52. Kliewer S A, Moore J T, Wade L, et al. An orphan nuclear receptor activated by p regnanes defines a novel steroid signaling pathway.[J] Cell, 1998, 92: 73 - 82.
53. Lehmann J M, McKee D D, WatsonM A, et al. The human orphan nuclear recep tor PXR is activated by compounds that regulate CYP3A4 gene exp ression and cause dru- interactions.[J] J Clin Invest, 1998, 102: 1016 - 23.
54. Chirulli V, Longo V, Marini S, et al. CAR and PXR exp ression and inducibility of CYP2B and CYP3A activities in rat and rabbitlungs.[ J ] L ife Sci, 2005, 76: 2535 - 46.
55. Miki Y, Suzuki T, Tazawa C, et al. Steroid and xenobiotic receptor ( SXR) , cytochrome P450 3A4 andmultidrug resistance gene 1in human adult and fetal tissues.[J] M ol Cell Endocrinol, 2005, 231: 75 - 85.
56. SouidiM, Gueguen Y, Linard C, et al. In vivo effects of chronic contamination with depleted uranium on CYP3A and associated nuclear receptors PXR and CAR in the rat. [J] Toxicology, 2005,214 (4): 113 - 22.
57. BauerB, HartzAM S, Fricker G, MillerD S. PregnaneX receptor up-regulation of P-glyc-orotein expression and transport function at the blood2brain barrier. [J] M ol Pharm acol, 2004,66 (14): 413- 9.
58. Masuyama H, Hiramatsu Y, Mizutani Y, et al. The exp ression of pregnane X recep tor and its target gene, cytochrome P450 3A1, in perinatalmouse.[J] Mol Cell Endocrinol, 2001; 172: 47 - 56.
59. Raucy JL. Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products.[J] Drug Metab Dispos, 2003; 31(4): 533 - 539.
60. Karl Bodin, Ulla Lindbom, Ulf Diczfalusy. Novel pathways of bile acid metabolism involving CYP3A4.[J] Biochimica et Biophysica Acta, 2005, 12(1687): 84– 93
61. Xiew , Barw ick J L , SimonC M , et al. Recip rocal activation of xenobiotic response genes by nuclear receptors SXR,PXR and CAR.[J] GenesDev, 2000, 14 (23): 3 014- 3 023
62. Michale EW, Erika B, Akiko U, et al. The environmental pollutant 1,2 dichoro22, 22bisethy -leneinduces rat hepatic cytochrome P450 2B and 3A expressionthroughthe constituteive androstane receptorand pregnane X receptor. [J] Mol Pharmacol, 2003, 64(12):474 - 481.
63. L ionel D, Ourlin JC, Pascussi JM, et al. Expression of CYP3A, CYP2B6, and CYP2C9 is regulated by the VitaminD receptor pathway in primary human hepatocyte.[J] J Biol Chem, 2002, 277: 25125 - 25132.
64. Ding XS, Jeff L. Induction of drug metabolism by forskolin, the role of the pregnane X receptor and PKA signal transduction pathway. [J] J Pharmacol Exp Ther,2005, 312: 849– 856
65. Ding XS, Jeff L. Repression of PXR-mediated induction of hepatic CYP3A gene expression by protein kinase C. [J] Biochem Pharmacol, 2005, 69: 867 - 873.
66.杨哲,陈仲清,蒋晓青,原位肝移植围术期细胞因子的变化.[J]广东医学,2006,27(8):1185-1187
67.张裕霞,张秀生,杜洪印,原位肝移植病人围术期凝血功能的变化.[J].中华麻醉学,2005,25(11):847-849
68.黑子清,罗晨芳,黎尚荣,肝硬化患者肝移植围术期血浆TXA2和PGI2水平变化.[J]中国病理生理杂志,Chinese Journal of Pathophysiology,2006, 22 (8) : 1650– 1653
69.罗晨芳,黑子清,罗刚肝移植围术期血浆一氧化氮和一氧化氮合酶活性的变化及意义.[J]中国病理生理杂志Chinese Journal of Pathophysiology.2005,21(11) :2229– 2232
70. Veroli P, O’Kelly B, Bertrand F, et al. Extrahepatic metabolism of propofol in man during the anhepatic phase of orthotopic liver transplantation.[J] Br J Anaesth, 1992, 68 (2) : 183 - 186.
71. Gao L, Ramzan I, Baker B. Rocuronium infusion requirements and plasma concentrationsat constant levels of neuromuscular paralysis during three phases of liver transplantation. [J] J Clin Anesth, 2003, 15 (4): 257 - 266.
72. Yang SP. Cytochrome P450 expression and activities in rat, rabbit and bovine tongue.[J] Comparative Biochemistry and Physiology Part C:Toxicology & Pharmacology, 2003, 136 (4): 297–308
73. M.F. Hebert. Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery.[J] Advanced Drug Delivery Reviews. 1997, (27): 201–214
74. Koichi Yokogawa, Tsutomu Shimada,Yasuhiko Higashi, et al.Modulation of mdrIa and CYP3A gene expression in the intestine and liver as possible cause of changes in thecyclo- sporine.[J] Biochemical Pharmacology,2002,63(12):777-783
75.王懋莉,李斌,张培建等,供体肝缺氧时间对肝移植大鼠生存率的影响.[J]江苏大学学报(医学版),2007,17(4):309-311.
76.吴建武,胡明政,杨小华等,不同术式大鼠原位肝移植模型的比较.[J]肝胆胰外科杂志,2007,19(1):18-21.
77. Chinsu Liu, Hsin-Lin Tsai, Taiwai Chin,et al, Clamping the Supra-Celiac Aorta Can Effectively Increase the Success Rate of Orthotopic Rat Liver Transplantation by Increasing the Tolerable Time of the Anhepatic Phase.[J] Journal of Surgical Research, 2006 ,136 (1):116–119
78.李美发.医药高效液相色谱技术。人民卫生出版社.1999,第一版
79.卢圣东.现代生物学实验技术.中国协和医科大学出版社.2004,第二版
80.覃杨.医学分子生物学实验指南.中国协和医科大学出版社.2004,第二版
81. Mather L E. Clinical pharmacokinetics of fentanyl and its newer derivatives. [J] Clin Pharmacokinet, 1983, 8 (5): 422 - 446.
82. Labroo R B, Painem F, Thummel K E, et al. Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: imp lications for interindividual variability in disposition, efficacy, and drug Interactions. [J] DrugMetab Dispos, 1997, 25 (9): 1072 - 1080.
83. Keams GL, Robinson PK, Wilson J T, et al. Cisapried disposition in neonates and infants: in vivo reflection of cytochromeP450 3A4 ontogeny.[J] Clin Pharmacol Ther ,2003 ,74 ( 4):312-325.
84. De Wildt SN, Keams GL, Leader J S, et al. Cytochrome P4503A: ontogeny and drug disposition. [J] Clin Pharmacokinet,1999, 37 (6): 4852505.
85. Paine MF, Khalighi M, Fisher JM, et al. Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism.[J] J Pharmacol Exp Ther, 1997, 283(3):1552 - 1562.
86. Johnson BM, Chen W, Borchardt RT, et al. A kinetic evaluation of the absorption, efflux, and metabolism of verapamil in the autoperfused rat jejunum.[J] J Pharmacol Exp Ther, 2003, 305(1):151– 158
87. Van-Obbergh LJ,Verbeeck RK,Michel I,et al.Extraphepatic metabolism of sevofluranein children undering orthotopic liver transplantation.[J] Anesthesiology.2000,92(3):683-687
88. Chow B,Bowden MI,Ho E,et al. Pharmaco-Kinetics and dynamics of atracurium infusions after paediatric orthotopic liver transplantantion.[J] Br J Anaesth. 2000,85(6):850-855
1. Bent LZ, Kroetz DL, Sheiner LB. Pharmacok kinetics: The dynamics of drug absorption, distribution, and elimination.[J] Goodman & Gilman’s the pharmacological basis of therapetics. NewYork : McGraw-Hill , 1996,12,(2):3～28
2. Wacher VJ, Silverman JA, Zhang Y et al. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidominetics.[J] J harm Sci , 1998,87(14):1322～30
3. Peyronneau MA, Renaud J P, Jaouen M et al. Expression in yeast of three allelic cDNAs coding for human liver P4503A4 different stabilities, binding properties and catalytic activites of the yeast-produced enzymes. Eur J Biochem , 1993 ,218(11):355～61
4. Jounaidi Y, Guzelian PS, Maurel P et al. Sequence of the 5-flanking region of CYP3A5: comparative analysis with CYP3A4 and CYP3A7.[J] Biochem Res Commun, 1994 ,205(5):1741～7
5.徐月萍.细胞色素P450酶系与药物代谢的相互作用.[J]中国药物与临床.2003,3(2):141-143
6. Kliewer SA, Moore JT, Wade L, et al. An orphannuclear recep tor activated by p regnanes defines a noval steroid signaling pathway. [J] Cell, 1998, 92(3): 73 - 82.
7. Lehmann J M, McKee D D, WatsonM A, et al. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene exp ression and cause drug interactions. [J] J Clin Invest, 1998, 102: 1016– 23
8. Chirulli V, Longo V, Marini S, et al. CAR and PXR exp ression and inducibility of CYP2B and CYP3A activities in rat and rabbit lungs. [J] Life Sci, 2005, 76: 2535 - 46.
9. Miki Y, Suzuki T, Tazawa C, et al. Steroid and xenobiotic receptor ( SXR) , cytochrome P450 3A4 andmultidrug resistance gene 1 in human adult and fetal tissues. [J]M ol Cell Endocrinol, 2005,231 (11): 75 - 85.
10. SouidiM, Gueguen Y, Linard C, et al. In vivo effects of chronic contamination with depleted uranium on CYP3A and associated nuclear recep tors PXR and CAR in the rat [J]. Toxicology, 2005,214 (25): 113 - 22.
11. BauerB, HartzAM S, Fricker G, MillerD S. Pregnane X receptor up-regulation ofP2glycop rotein exp ression and transport function at the blood2brain barrier. [J] M ol Pharm acol, 2004, 66(13): 413- 9.
12. Xie W, Barwick JL, Downes M, et al. Humanized xenobiotic response in mice exp ressing nuclear receptor SXR. [J] Nature, 2000, 406(36): 435 - 439.
13. Phillip s A, Hood SR, Gibson GG, et al. Impact of transcrip tion factor p rofile and chromatin conformation on human hepatocyte CYP3A gene exp ression. [J] Drug Metab Dispos, 2005, 33(41): 233– 242
14. Song X, Xie M, Zhang H, et al. The p regnane X receptor binds to response elements in a genomic context-dependent manner and PXR activators rifamp icinselectively alters the binding among target genes. [J] DrugMetab Dispos, 2004, 32(5): 35 - 42.
15. Michale EW, Erika B, Akiko U, et al. The environmental pollutant 1, 12dichoro22, 22bis ethylene induces rat hepatic cytochrome P450 2B and 3A expression through the constituteive androstane receptor and pregnane X receptor. [J] Mol Pharmacol, 2003, 64(9):474– 481
16. L ionel D, Ourlin JC, Pascussi JM, et al. Exp ression of CYP3A, CYP2B6, and CYP2C9 is regulated by the Vitamin D receptor pathway in p rimary human hepatocyte. [J] J Biol Chem, 2002, 277(8): 25125– 25132
17. Rommel G, LeeW, Brenda F, et al. The orphan nuclear receptor HNF4αdetermines PXR2 and CAR2mediated xenobiotic induction of CYP3A4. [J]. NatMed, 2003, 9(11):220 - 224.
18. Rodrigues E, Vilarem MJ, Ribeiro V, et al. Two CCAAT/ enhancer binding protein sites in the cytochrome P4503A1l ocus.[J]. Eur J Biochem, 2003, 270: 556 -564.
19. Ding XS, Jeff L. Induction of drug metabolism byforskolin, the role of the pregnane X receptor and PKAsignal transduction pathway. [J] J Pharmacol Exp Ther, 2005, 312(14): 849 - 856.
20. Ding XS, Jeff L. Repression of PXR-mediated induction of hepatic CYP3A gene exp ression by p rotein kinase C.[J] Biochem Pharmacol, 2005, 69(23): 867 - 873.
21. Jasminder S, Mark A, Zheng XX, et al. Avasimibeinduces CYP3A4 and multiple drug resistance protein 1 gene expression through activation of the pregnane X receptor. [J] J Pharmacol Exp Ther, 2003, 306(14): 1027 -1034
22. Staudinger JL, Goodwin B, Jones SA, et al. The nuclear receptor PXR is a lithocholocacid sensor that protects against liver toxicity. [J] Proc Natl Acad Sci USA, 2001, 98(22): 3369 - 3374.
23. Patel NH, Rothenberg ML. Multidrug resistance in cancer chemotherapy. [J ] Invest New Drugs, 1994, 12(1) :1 - 13.
24. Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. [J]. Annu RevBiochem, 1993, 62(34):385 - 427.
25. Parreboom A, Van Asperen J, Mayer U et al. Limited oral bioavailability and active eothelial excertion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci USA , 1997 ;94(11):2031～5
26. Meerm Terwogt JM, Beijnen J H, ten Bokkel Huinink WW et al. Coadiministration of cyclosporin enables oral therapy with paclitaxel. L ancet , 1998 ;352(25) :285。
27. Lwn KS, Mayo RR, Leichtman AB et al. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporinr A. Cli n Pharmacol Ther, 1997,62 (36):248～60
28. Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochome P450 3A and P-glycoprotein: Implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog, 1995 ,13(5):129～34
29. Benet LZ, Izumi T, Zhang Y et al. Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery. [J] Controlled Release, 1999,62(13):25～31
30. Wu CY, Benet LZ, Hebert MF, et al. Differentiation of absorption and first2pass gut and hepatic metabolism in humans: studies with cyclosporine [J]. Clin Pharmacol Ther, 1995, 58(5):492 - 497.
31. Johnson BM, Chen W, Borchardt RT, et al. A kinetic evaluation of the absorption, efflux, and metabolismof verapamil in the autoperfused rat jejunum. [J] J Pharmacol Exp Ther, 2003, 305(1):151– 158
2.周宏灏,主编.遗传药理学.[M]第二版.北京:科学出版社,2001 : 53 - 235.
3. Huynh NH, Tyrefors N, Ekman L, Johansson M. Determination of fentanyl in human plasma and fentanyl and norfentanyl in human urine using LC–MS/MS.[J] Journal of Pharmaceutical and Biomedical Analysis, 2005, 37 (5):1095-1100
4. Lahoz A. Determination of major human cytochrome P450s activities in 96-well plates using liquid chromatography tandem mass spectrometry. [J] Toxicology in Vitro, 2007, 21 (7): 1247–1252
5.宋振玉,刘耕陶.当代药理学.[M]北京:中国协和医科大学联合出版社, 1994
6. Krishna D R, Klotz U. Extrahepatic metabolism of drug in humans.[J] Clin Pharmacokinet, 1994, 26:1442-1601
7.王羽,药物的肝外代谢. [J]药学进展, 2004 , 28(7): 289-293
8. Morgan A R et al. Metablism and Disposition. [J] Drug, 1998, 26(12):1232-1236
9. Jin Mj. Contributions of intestinal P-glycoprotein and CYP3A to oral bioavailability of cyclosporin A in mice treated with or without dexamethas. [J] International journal opharmaceutics,2006 , 309 (12):81-86
10. Xu DX, Wei W, Sun MF, et al. Kupffer cells and ROS partially mediate LPS-induced down-regulation of nuclear receptor Pregnane X receptor and its target gene CYP3A in mouse liver. [J] Free Radic BiolMed, 2004, 37 (1): 10 - 22.
11. Kanokwan, Jarukamjorn. Modified expression of cytochrome P450 mRNAs by growth hormone in mouse liver. [J] Toxicology, 2006, 219 (13):97–105
12. Staudinger JL, Goodwin B, Jones SA, et al. The nuclear receptor PXR is a lithocholoc acid sensor that protects against liver toxicity.[J] Proc Natl Acad Sci USA, 2001, 98 (7): 3369 - 3374.
13. Prajakti A, kothare, Cheryl L, et al. Intestinal metabolism: the role of enzyme localization in phenol metabolism kinetics.[J] Drug Metab Dispos, 2002, 30 (5):586-594.
14.顾健腾,陶国才,鲁开智,等.大鼠肾脏异丙酚代谢相关ugt1a6基因在无肝期表达变化的研究. [J]第三军医大学学报, 2005,27 (16) : 1697– 1699)
15. Zhao Lin, Li Lin-Fang, Wu Meng-Chao An in vivo rat model for assessment of extrahepatic metabolism. [J] Journal of Pharmacological and Toxicological Methods, 2001, (45): 181– 185
16.张红,方熠,王淑君等,高效液相色谱法测定人血浆中芬太尼的浓度.[J]同济大学学报(医学版),2005,26(1):49-50
17.李正翔,赵晴,董伟林,高效液相色谱法测定人血浆中芬太尼浓度.[J]中国医院药学杂志,2004,24(10):607-609
18. Habib Bagheri, Ali Es-haghi, Faezeh Khalilian et al. Determination of fentanyl in human plasma by head-space solid-phasemicroextr action and gas chromatography–mass spectrometry.[J] Journal of Pharmaceutical and Biomedical Analysis 2007,43 (12) :1763–1768
19. Hak Soo Choia, Ho-Chul Shinb, Gilson Khanga, et al.Quantitative analysis of fentanyl in rat plasma by gas chromatography with nitrogen–phosphorus detection.[J] Journal of Chromatography 2001, 765 (B): 63–69
20. J.Guitton, M.Desage, S.Alamercery, et al. Gas chromatographic-mass spectrometry and gas chromatographic-Fourier transform infrared spectroscopy assay for the simultaneous identification of fentanyl metabolites.[J] Joural of chromatography 1997,59 (b):59-70
21.张利萍,张现化,张蕾等,LC/MS/MS联用技术测定全血中瑞芬太尼浓度.[J]中国新药杂志,2006,15(2):137-139
22. Yi-Wei Chang, Hsien-Tsung Yao, Yu-Sheng Chao,et al Rapid and sensitive determination of fentanyl in dog plasma by on-line solid-phase extraction integrated with a hydrophilic column coupled to tandem mass spectrometry.[J] Journal of Chromatography B, 2007 (857) 195–201
23. Joel G.Hardman, Alfred Goodman The Pharmacological Basis of Therapetics第10版:465-467
24. Shafer, S. L, Varvel, J.R., Aziz, N. et al.Pharmacokinetics of fentanyl administred by computercontrolled infusion pump.[J] Anesthesiology, 1990,73:1091-1102
25.庄心良,曾因明,陈伯銮.现代麻醉学.人民卫生出版社.2003,第三版
26.顾健腾,陶国才,易斌等.持续恒速输注异丙酚在大鼠无肝期前后血药浓度变化的研究.[J]第三军医大学学报, 2005,27 (17) : 1766–1769
27.张蕾,张利萍,张现化等,原位肝移植患者静注瑞芬太尼的药代动力学.[J]中国临床药理学杂志,2007,23(6):437-441
28. Rendic S. Summary of information on human CYP enzymes: human P450 metabolism data. [J] D rug Metab Rev, 2002; 34: 83– 448
29. NebertDW, AdesnikM, CoonMJ, et al. The P450 gene superfamily: recommended nomenclature. [J] DNA, 1987; 6: 1 - 11.
30.徐启明,李文硕,临床麻醉学.人民卫生出版社.2000,第一版
31. De Waziers I, Cugnenc P H, Yang C S et al. Cytochorome P450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues.[J] Pharm.Exp.Ther.1990, 258:387-391
32.姚欣,钱元恕.肝外药物代谢酶的研究进展.[J]国外医学药学分册,2003 , 30(2) :97-101
33.冷星夫,邱星辉.细胞色素P450酶系的结构、功能与应用前景,科学出版社.2001,56-69
34. Zhang Y, Benet LZ. The gut as a drug absorption: combined role of cytochrome P450 3A and p-glycoprotein. [J] Clin Pharmacokinet, 2001, 40 (3):159 - 168.
35. Shin-Pei Yang, Theresa Medling, Gregory M. Raner. Cytochrome P450 expression and activities in rat, rabbit and bovine tongue.[J] Comparative Biochemistry and Physiology Part C, 2003,136 (22) 297–308.
36. Paine MF, Schmiedlin2Ren P, Watkins PB. Cytochrome P450 1A1 expression in human small bowel: interindividual variation and inhibition by ketoconazole. [J] Drug Metab Dispos , 1999 , 27(3) :360– 364
37. Yoshihiro Konno, Masashi Sekimoto, Kiyomitsu Nemoto.et al Sex difference in induction of hepatic CYP2B and CYP3A subfamily enzymes by nicardipine and nifedipine in rats.[J] Toxicology and Applied Pharmacology, 2004,6(19): 20– 28
38. Tsutomu Shimada, Koichi,okogawa, Masaaki Nomur.Site-dependent contributions of P-glycoprotein and CYP3A to cyclosporin A absorption, and effect of dexamethasone in small intestine of mice.[J] Biochemical Pharmacology,2006,72 (8):1042-1050
39.张宾,周晰.黄芪对糖尿病大鼠CYP450酶系活性的影响.[J]中药药理与临床.2007,23(4):36-38
40.李平,程建峰,陈东鸿等.地塞米松、苯巴比妥钠和利多卡因对昆明种小鼠肝P450 3A酶的影响.[J]第四军医大学学报,2001,22(1):26-28
41.余爱荣,辛华雯,吴笑春等.环孢素A与盐酸小檗碱合用对大鼠肝脏和小肠药物代谢酶的影响.[J]中国医院药学杂志,2005, 25 (2):104-106
42.曹安民,施畅,刘雁等.酮康唑对大鼠肝脏CYP450酶系的影响.[J]中国新药杂志.2007,16(4):285-287
43. Amaia Irizar, Costas Ioannides, Marked inhibition of hepatic cytochrome P450 activity in cholesterol-induced atherosclerosis in rabbits. [J] Toxicology 1998 (126) :179–193
44. Liddle C, Goodwin B J, George J et al. Separate and interactive regulation of cytochrome P4503A4 by triiodothyronine dexamethasone and groth hormone in cultured hepatocytes.[J] Clin. Endocrinol. Metab.1998,83 (2):2411-2416
45. Peterson TC, Hodgson P, Fernandez2Salguero P , Neumeister M, Gonalez FJ . Hepatic fibrosis and cytochrome P450: experimental models of fibrosis compared to AHR knockoutmice. [J] Hepatol Res, 2000, 17 (2):112 - 125.
46. Wang H, Chen M, Liao ZX. Changes of liver xenobiotic-metabolizing function at the different status of hepatic injury.[J] Chin Pharmacol Bull (中国药理学报) , 2004 , 20(7) :772 - 775.
47. Wang XD , Ar′Rajab A , Andersson R , Soltesz V , Wang W, Svensson M, et al . The influ- -ence of surgically induced acute liver failure on the intestine in the rat.[J] Scand J Gastroenterol, 1993, 28 (1):31 - 40.
48. Kasravi FB , Wang L , Wang XD , Molin G, Bengmark S ,Jeppsson B.Bacterial translocation in acute liver injury induced by D-galactosamine.[J] Hepatology, 1996, 23 (1) :97 - 103.
49.胡小玲,汪晖,吴基良等.肝纤维化状态下小肠药物代谢功能的改变.[J]中国药理学与毒理学杂志,2004,18(5):379-384
50. Peter A.Chr. Hoen, Jan N. M. Commandeur. Selective Induction of Cytochrome P450 3A1 by Dexamethasone in Cultured Rat Hepatocytes.[J] Biochemical Pharmacology, 2000, ,60 (2):1059-1518
51. Tsutomu Sakuma, Yusuke Endo, Misae Mashino.et al Regulation of the expression of two female-predominant CYP3AmRNAs in mouse liver by sex and growthhormones.[J] Archives of Biochemistry and Biophysics,2002,404(2):234-242
52. Kliewer S A, Moore J T, Wade L, et al. An orphan nuclear receptor activated by p regnanes defines a novel steroid signaling pathway.[J] Cell, 1998, 92: 73 - 82.
53. Lehmann J M, McKee D D, WatsonM A, et al. The human orphan nuclear recep tor PXR is activated by compounds that regulate CYP3A4 gene exp ression and cause dru- interactions.[J] J Clin Invest, 1998, 102: 1016 - 23.
54. Chirulli V, Longo V, Marini S, et al. CAR and PXR exp ression and inducibility of CYP2B and CYP3A activities in rat and rabbitlungs.[ J ] L ife Sci, 2005, 76: 2535 - 46.
55. Miki Y, Suzuki T, Tazawa C, et al. Steroid and xenobiotic receptor ( SXR) , cytochrome P450 3A4 andmultidrug resistance gene 1in human adult and fetal tissues.[J] M ol Cell Endocrinol, 2005, 231: 75 - 85.
56. SouidiM, Gueguen Y, Linard C, et al. In vivo effects of chronic contamination with depleted uranium on CYP3A and associated nuclear receptors PXR and CAR in the rat. [J] Toxicology, 2005,214 (4): 113 - 22.
57. BauerB, HartzAM S, Fricker G, MillerD S. PregnaneX receptor up-regulation of P-glyc-orotein expression and transport function at the blood2brain barrier. [J] M ol Pharm acol, 2004,66 (14): 413- 9.
58. Masuyama H, Hiramatsu Y, Mizutani Y, et al. The exp ression of pregnane X recep tor and its target gene, cytochrome P450 3A1, in perinatalmouse.[J] Mol Cell Endocrinol, 2001; 172: 47 - 56.
59. Raucy JL. Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products.[J] Drug Metab Dispos, 2003; 31(4): 533 - 539.
60. Karl Bodin, Ulla Lindbom, Ulf Diczfalusy. Novel pathways of bile acid metabolism involving CYP3A4.[J] Biochimica et Biophysica Acta, 2005, 12(1687): 84– 93
61. Xiew , Barw ick J L , SimonC M , et al. Recip rocal activation of xenobiotic response genes by nuclear receptors SXR,PXR and CAR.[J] GenesDev, 2000, 14 (23): 3 014- 3 023
62. Michale EW, Erika B, Akiko U, et al. The environmental pollutant 1,2 dichoro22, 22bisethy -leneinduces rat hepatic cytochrome P450 2B and 3A expressionthroughthe constituteive androstane receptorand pregnane X receptor. [J] Mol Pharmacol, 2003, 64(12):474 - 481.
63. L ionel D, Ourlin JC, Pascussi JM, et al. Expression of CYP3A, CYP2B6, and CYP2C9 is regulated by the VitaminD receptor pathway in primary human hepatocyte.[J] J Biol Chem, 2002, 277: 25125 - 25132.
64. Ding XS, Jeff L. Induction of drug metabolism by forskolin, the role of the pregnane X receptor and PKA signal transduction pathway. [J] J Pharmacol Exp Ther,2005, 312: 849– 856
65. Ding XS, Jeff L. Repression of PXR-mediated induction of hepatic CYP3A gene expression by protein kinase C. [J] Biochem Pharmacol, 2005, 69: 867 - 873.
66.杨哲,陈仲清,蒋晓青,原位肝移植围术期细胞因子的变化.[J]广东医学,2006,27(8):1185-1187
67.张裕霞,张秀生,杜洪印,原位肝移植病人围术期凝血功能的变化.[J].中华麻醉学,2005,25(11):847-849
68.黑子清,罗晨芳,黎尚荣,肝硬化患者肝移植围术期血浆TXA2和PGI2水平变化.[J]中国病理生理杂志,Chinese Journal of Pathophysiology,2006, 22 (8) : 1650– 1653
69.罗晨芳,黑子清,罗刚肝移植围术期血浆一氧化氮和一氧化氮合酶活性的变化及意义.[J]中国病理生理杂志Chinese Journal of Pathophysiology.2005,21(11) :2229– 2232
70. Veroli P, O’Kelly B, Bertrand F, et al. Extrahepatic metabolism of propofol in man during the anhepatic phase of orthotopic liver transplantation.[J] Br J Anaesth, 1992, 68 (2) : 183 - 186.
71. Gao L, Ramzan I, Baker B. Rocuronium infusion requirements and plasma concentrationsat constant levels of neuromuscular paralysis during three phases of liver transplantation. [J] J Clin Anesth, 2003, 15 (4): 257 - 266.
72. Yang SP. Cytochrome P450 expression and activities in rat, rabbit and bovine tongue.[J] Comparative Biochemistry and Physiology Part C:Toxicology & Pharmacology, 2003, 136 (4): 297–308
73. M.F. Hebert. Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery.[J] Advanced Drug Delivery Reviews. 1997, (27): 201–214
74. Koichi Yokogawa, Tsutomu Shimada,Yasuhiko Higashi, et al.Modulation of mdrIa and CYP3A gene expression in the intestine and liver as possible cause of changes in thecyclo- sporine.[J] Biochemical Pharmacology,2002,63(12):777-783
75.王懋莉,李斌,张培建等,供体肝缺氧时间对肝移植大鼠生存率的影响.[J]江苏大学学报(医学版),2007,17(4):309-311.
76.吴建武,胡明政,杨小华等,不同术式大鼠原位肝移植模型的比较.[J]肝胆胰外科杂志,2007,19(1):18-21.
77. Chinsu Liu, Hsin-Lin Tsai, Taiwai Chin,et al, Clamping the Supra-Celiac Aorta Can Effectively Increase the Success Rate of Orthotopic Rat Liver Transplantation by Increasing the Tolerable Time of the Anhepatic Phase.[J] Journal of Surgical Research, 2006 ,136 (1):116–119
78.李美发.医药高效液相色谱技术。人民卫生出版社.1999,第一版
79.卢圣东.现代生物学实验技术.中国协和医科大学出版社.2004,第二版
80.覃杨.医学分子生物学实验指南.中国协和医科大学出版社.2004,第二版
81. Mather L E. Clinical pharmacokinetics of fentanyl and its newer derivatives. [J] Clin Pharmacokinet, 1983, 8 (5): 422 - 446.
82. Labroo R B, Painem F, Thummel K E, et al. Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: imp lications for interindividual variability in disposition, efficacy, and drug Interactions. [J] DrugMetab Dispos, 1997, 25 (9): 1072 - 1080.
83. Keams GL, Robinson PK, Wilson J T, et al. Cisapried disposition in neonates and infants: in vivo reflection of cytochromeP450 3A4 ontogeny.[J] Clin Pharmacol Ther ,2003 ,74 ( 4):312-325.
84. De Wildt SN, Keams GL, Leader J S, et al. Cytochrome P4503A: ontogeny and drug disposition. [J] Clin Pharmacokinet,1999, 37 (6): 4852505.
85. Paine MF, Khalighi M, Fisher JM, et al. Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism.[J] J Pharmacol Exp Ther, 1997, 283(3):1552 - 1562.
86. Johnson BM, Chen W, Borchardt RT, et al. A kinetic evaluation of the absorption, efflux, and metabolism of verapamil in the autoperfused rat jejunum.[J] J Pharmacol Exp Ther, 2003, 305(1):151– 158
87. Van-Obbergh LJ,Verbeeck RK,Michel I,et al.Extraphepatic metabolism of sevofluranein children undering orthotopic liver transplantation.[J] Anesthesiology.2000,92(3):683-687
88. Chow B,Bowden MI,Ho E,et al. Pharmaco-Kinetics and dynamics of atracurium infusions after paediatric orthotopic liver transplantantion.[J] Br J Anaesth. 2000,85(6):850-855
1. Bent LZ, Kroetz DL, Sheiner LB. Pharmacok kinetics: The dynamics of drug absorption, distribution, and elimination.[J] Goodman & Gilman’s the pharmacological basis of therapetics. NewYork : McGraw-Hill , 1996,12,(2):3～28
2. Wacher VJ, Silverman JA, Zhang Y et al. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidominetics.[J] J harm Sci , 1998,87(14):1322～30
3. Peyronneau MA, Renaud J P, Jaouen M et al. Expression in yeast of three allelic cDNAs coding for human liver P4503A4 different stabilities, binding properties and catalytic activites of the yeast-produced enzymes. Eur J Biochem , 1993 ,218(11):355～61
4. Jounaidi Y, Guzelian PS, Maurel P et al. Sequence of the 5-flanking region of CYP3A5: comparative analysis with CYP3A4 and CYP3A7.[J] Biochem Res Commun, 1994 ,205(5):1741～7
5.徐月萍.细胞色素P450酶系与药物代谢的相互作用.[J]中国药物与临床.2003,3(2):141-143
6. Kliewer SA, Moore JT, Wade L, et al. An orphannuclear recep tor activated by p regnanes defines a noval steroid signaling pathway. [J] Cell, 1998, 92(3): 73 - 82.
7. Lehmann J M, McKee D D, WatsonM A, et al. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene exp ression and cause drug interactions. [J] J Clin Invest, 1998, 102: 1016– 23
8. Chirulli V, Longo V, Marini S, et al. CAR and PXR exp ression and inducibility of CYP2B and CYP3A activities in rat and rabbit lungs. [J] Life Sci, 2005, 76: 2535 - 46.
9. Miki Y, Suzuki T, Tazawa C, et al. Steroid and xenobiotic receptor ( SXR) , cytochrome P450 3A4 andmultidrug resistance gene 1 in human adult and fetal tissues. [J]M ol Cell Endocrinol, 2005,231 (11): 75 - 85.
10. SouidiM, Gueguen Y, Linard C, et al. In vivo effects of chronic contamination with depleted uranium on CYP3A and associated nuclear recep tors PXR and CAR in the rat [J]. Toxicology, 2005,214 (25): 113 - 22.
11. BauerB, HartzAM S, Fricker G, MillerD S. Pregnane X receptor up-regulation ofP2glycop rotein exp ression and transport function at the blood2brain barrier. [J] M ol Pharm acol, 2004, 66(13): 413- 9.
12. Xie W, Barwick JL, Downes M, et al. Humanized xenobiotic response in mice exp ressing nuclear receptor SXR. [J] Nature, 2000, 406(36): 435 - 439.
13. Phillip s A, Hood SR, Gibson GG, et al. Impact of transcrip tion factor p rofile and chromatin conformation on human hepatocyte CYP3A gene exp ression. [J] Drug Metab Dispos, 2005, 33(41): 233– 242
14. Song X, Xie M, Zhang H, et al. The p regnane X receptor binds to response elements in a genomic context-dependent manner and PXR activators rifamp icinselectively alters the binding among target genes. [J] DrugMetab Dispos, 2004, 32(5): 35 - 42.
15. Michale EW, Erika B, Akiko U, et al. The environmental pollutant 1, 12dichoro22, 22bis ethylene induces rat hepatic cytochrome P450 2B and 3A expression through the constituteive androstane receptor and pregnane X receptor. [J] Mol Pharmacol, 2003, 64(9):474– 481
16. L ionel D, Ourlin JC, Pascussi JM, et al. Exp ression of CYP3A, CYP2B6, and CYP2C9 is regulated by the Vitamin D receptor pathway in p rimary human hepatocyte. [J] J Biol Chem, 2002, 277(8): 25125– 25132
17. Rommel G, LeeW, Brenda F, et al. The orphan nuclear receptor HNF4αdetermines PXR2 and CAR2mediated xenobiotic induction of CYP3A4. [J]. NatMed, 2003, 9(11):220 - 224.
18. Rodrigues E, Vilarem MJ, Ribeiro V, et al. Two CCAAT/ enhancer binding protein sites in the cytochrome P4503A1l ocus.[J]. Eur J Biochem, 2003, 270: 556 -564.
19. Ding XS, Jeff L. Induction of drug metabolism byforskolin, the role of the pregnane X receptor and PKAsignal transduction pathway. [J] J Pharmacol Exp Ther, 2005, 312(14): 849 - 856.
20. Ding XS, Jeff L. Repression of PXR-mediated induction of hepatic CYP3A gene exp ression by p rotein kinase C.[J] Biochem Pharmacol, 2005, 69(23): 867 - 873.
21. Jasminder S, Mark A, Zheng XX, et al. Avasimibeinduces CYP3A4 and multiple drug resistance protein 1 gene expression through activation of the pregnane X receptor. [J] J Pharmacol Exp Ther, 2003, 306(14): 1027 -1034
22. Staudinger JL, Goodwin B, Jones SA, et al. The nuclear receptor PXR is a lithocholocacid sensor that protects against liver toxicity. [J] Proc Natl Acad Sci USA, 2001, 98(22): 3369 - 3374.
23. Patel NH, Rothenberg ML. Multidrug resistance in cancer chemotherapy. [J ] Invest New Drugs, 1994, 12(1) :1 - 13.
24. Gottesman MM, Pastan I. Biochemistry of multidrug resistance mediated by the multidrug transporter. [J]. Annu RevBiochem, 1993, 62(34):385 - 427.
25. Parreboom A, Van Asperen J, Mayer U et al. Limited oral bioavailability and active eothelial excertion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci USA , 1997 ;94(11):2031～5
26. Meerm Terwogt JM, Beijnen J H, ten Bokkel Huinink WW et al. Coadiministration of cyclosporin enables oral therapy with paclitaxel. L ancet , 1998 ;352(25) :285。
27. Lwn KS, Mayo RR, Leichtman AB et al. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporinr A. Cli n Pharmacol Ther, 1997,62 (36):248～60
28. Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochome P450 3A and P-glycoprotein: Implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog, 1995 ,13(5):129～34
29. Benet LZ, Izumi T, Zhang Y et al. Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery. [J] Controlled Release, 1999,62(13):25～31
30. Wu CY, Benet LZ, Hebert MF, et al. Differentiation of absorption and first2pass gut and hepatic metabolism in humans: studies with cyclosporine [J]. Clin Pharmacol Ther, 1995, 58(5):492 - 497.
31. Johnson BM, Chen W, Borchardt RT, et al. A kinetic evaluation of the absorption, efflux, and metabolismof verapamil in the autoperfused rat jejunum. [J] J Pharmacol Exp Ther, 2003, 305(1):151– 158
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