儿童环孢素群体药动学研究以及发育对大鼠CYP3A和核受体表达的影响
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摘要
目的
建立CsA治疗再生障碍性贫血(再障)儿童的群体药动学模型,考察其群体药物动力学特征,为临床调整个体用药提供方法。
方法
利用前瞻性调查分析方法,收集浙江大学医学院附属儿童医院222例门诊再障患儿1611个全血稳态谷浓度样本,用NONMEM程序建立群体药物动力学模型,定量考察年龄、身高、体重、BSA、GFR、合并用药强的松、司坦唑醇等固定效应对药物动力学参数的影响。
结果
CsA稳态谷浓度药物动力学参数能用米-曼氏模型进行较好的拟合,用建模组获得的群体参数在验证组中有较理想的拟合优度。模型中最终保留了年龄、体表面积(BSA)、肾小球滤过率(GFR)、和司坦唑醇合并用药4个固定效应,米-曼氏模型参数V_m和K_m为206(mg/d)、39.9(μg/L),V_m和K_m的个体间变异分别是28.0%和67.7%,个体自身的变异为29.2%。
用全数据集模拟的最终模型为:DR=[206+9.64×(AGE-8.26)+225×(BSA-1.06)]×Exp(η_1)×Css/({[39.9+3.61×(GFR-1565)]×(1+0.868×STZ)}×Exp(η_2)+Css)+ε
结论
环孢素治疗儿童再障具有明显的年龄依赖性的药动学变化特征。用本研究所得到的群体药物动力学模型结合Bayesian反馈法可以为临床儿童血液病患儿CsA的个体化用药提供方法。
目的:
初步研究不同出生体重新生大鼠CYP3A1/2、PXR、CAR和HNF4α表达差异及其影响CYP3A1/2的调控因素。
方法:
怀孕第2天的SD孕鼠,随机分配入自由进食组(nourished rats;NR)和营养限制组(undernourished rats,UR),NR组母鼠所生仔鼠,且体重在5.2～7.2g之间的为正常出生体重组(normal birth weight group,NBW,n=15);UR组母鼠所生仔鼠且体重＜5.2g为低出生体重组(low birth weight group,LBW,n=15)。NR组母鼠所生仔鼠且体重＞7.2g的新生大鼠为HBW(High birth weight group,HBW,n=15)组。
Real-time RT-PCR方法测定CYP3A1/2、PXR、CAR和HNF4α肝组织mRNA表达。免疫组织化学方法检测CYP3A1/2,CAR和HNF4α蛋白表达和组织定位,对染色强度和阳性细胞数计分后评价蛋白表达差异。
结果
低出生体重显著影响了CYP3A2和CAR的mRNA表达以及CYP3A1和CAR的蛋白表达。而高出生体重显著影响了CYP3A2和HNF4α的mRNA水平,以及CYP3A1和HNF4α的蛋白表达水平。CYP3A1的mRNA与CYP3A2和HNF4α的mRNA的表达具有相关性。
结论
出生体重对CYP3A1/2以及核受体的表达具有不同程度的影响。提示,需注意不同出生体重新生儿对药物的反应性差异。
目的
研究不同发育阶段、高脂饮食状态下CYP3A1/2以及核受体的表达变化规律。探讨影响发育过程中CYP3A1/2表达调控的重要因素。
方法
LBW模型建立、mRNA和蛋白测定方法同本章第一节。
模型分组:
NBW-常规饲料组(normal birth weight-normal diet group,NN组)
NBW-高脂饲料组(normal birth weight-high lipid and high energy group,NH组)
LBW-常规饲料组(low birth weight-normal diet group,LN组)
LBW-高脂饲料组(loW birth weight-high lipid and high energy group,LH组)
以上各组大鼠分别在生后3、7、14、21、28、56和84天收集肝脏(n=6-8/组)。
结果
CYP3A1/2以及核蛋白PXR、CAR、HNF4α的表达具有年龄依赖性。低出生体重可以改变代谢酶和核受体表达并且一直持续到成年期,其中对PXR/CAR的改变尤为明显,而且在很大程度上与CYP3A1/2表达相关。高脂饮食可以改变代谢酶和核受体的表达,其中HNF4α基因表达的改变最为显著。
结论
发育过程中CYP3A以及相关核受体表达的改变和相互作用,会导致机体对物质代谢的变化,影响治疗药物的安全性和药物相互作用,临床上需关注低出生体重和肥胖患儿的合理用药。
Objectives
The aim of this study was to develop a population pharmacokinetic model of cyclosporin(CsA) in pediatric aplastic anemia patients,thereby optimizing its therapeutic effects in clinical trials.
Methods
We have prospectively collected 1611 routine samples of average steady-state CsA trough concentration in 222 pediatric patients with hematologic disease in a Chinese population.These data were analyzed using the nonlinear mixed-model program(NONMEM).Based on the influence of numerous tested covariates(i.e.,age, height,weight,BSA,GFR),a population pharmacokinetic model of CsA was developed and further validated by data splitting.
Results
After oral administration,the whole blood steady-state trough concentration of CsA could be well described by a Michaelis-Menten model,in which four covariates (i.e.,age,BSA,GFR,and stanozolol) were included.Furthermore,the Michaelis-Menten constants,Vm and Km with interindividual variation in parenthesis, were estimated to be 206 mg/d(28%) and 39.9μg/L(67.7%),respectively.The intraindividual variation of V_m and K_m was 29.2%.
The final model was described as: DR=([206+9.64×(AGE-8.26)+22.5×(BSA-1.06)]×Exp(η_1)×Css)/({[39.9+3.6l×(GFR-1565]×(1+0.868×STZ)}×Exp(η_2)+Css)+ε
Conclusions
In conclusion,pharrnacokinetic parameters of CsA in pediatric aplastic anemia patients may be largely influenced by age,BSA,GFR and Stanzolol.We propose that our CsA population pharrnaeokinetie model,combined with the Bayesian forecasting method,may optimize the dosage of CsA in clinical trials.
Objectives
The aim of this study was to investigate the effects of birth weight on the expression and regulation of CYP3A1/2 as well as its nuclear receptors,including PXR, CAR,and HNF4a in newborn rats.
Methods
Pregnant rats were randomly divided into two groups:nourished and under-nourished.The offspring of nourished rats with birth weight between 5.2～7.2g were defined as normal-birth-weight group(NBW,n=15),while those of undernourished rats with birth weight under 5.2g were defined as low-birth-weight group(LBW,n=15).Additionally,the offspring of nourished rats with birth weight above 7.2g were defined as high-birth-weight group(HBW,n=15).
Hepatic mRNA expression of CYP3A1,PXR.,CAR and HNF4αwas detected by quantitative real-time RT-PCR.Immunohistochemistry was performed to investigate the corresponding protein expression and localization.Protein expression was evaluated by using a score corresponding to the sum of both staining intensity and percentage of positive hepatocytes.
Results
Low birth weight could significantly affect mRNA expression of CYP3A2 and CAR,and protein expression of CYP3A1 and CAR.In contrast,the high birth weight could significant affect the mRNA levels of CYP3A2 and HNF4α,and also the protein levels of CYP3A1 and HNF4a expression.CYP3A1 mRNA expression correlated with that of CYP3A2 and HNF4a.
Conclusions
In conclusion,birth weight could influence the production of several drug metabolism enzymes(i.e.,CYP3A1/2,and its nuclear receptors) in newborn rats, which should be taken into consideration when delivering medication to LBW and HBW infants in humans.
Objectives
In this study,we have aimed to investigate the effects of low birth weight and high-lipid diet on the expression and regulation of CYP3A1/2 as well as its nuclear receptors,including PXR,CAR,and HNF4α,in female rats during development.
Methods
The LBW animal model was established as mentioned above in Part One.Gene expression analysis(mRNA and protein levels) was performed as described previously. According to different birth weight and diet feeding,rats were divided into 4 groups as following:
1.Normal birth weight-normal diet group,NN-group
2.Normal birth weight-high lipid and high energy group,NH-group
3.Low birth weight-normal diet group,LN-group
4.Low birth weight-high lipid and high energy group,LH-group
Livers were isolated from each group,and subsequently used for gene expression study (i.e.,mRNA and protein levels) at 3,7,14,21,28,56,84 days after birth(n=6-8 per group).
Results
The hepatic expression of CYP3A1/2 and its nuclear receptors(i.e.,PXR,CAR, and HNF4α) was found to be age'dependent in rats.The effects of low birth weight on the expression of CYP3A1/2,PXR,CAR and HNF4αcan persist after birth.In particular,the expression of PXR and CAR was dramatically altered under the LBW situation,which was correlated with the expression of CYP3A1/2.Furthermore,the expression of CYP3A1/2 and their nuclear receptors,especially the HNF4α,was largely influenced by the high-lipid diet feeding in rats.
Conclusion
In conclusion,the hepatic expression and modulation of CYP3A1/2 and its nuclear receptors(i.e.,PXR,CAR,and HNF4α) were influenced by both birth weight and high-lipid diet feeding in developing rats.We propose that the alteration and interaction of CYP3A and its nuclear receptors have potential clinical implications for optimal medication in low birth weigh and fat children.
建立CsA治疗再生障碍性贫血(再障)儿童的群体药动学模型,考察其群体药物动力学特征,为临床调整个体用药提供方法。
方法
利用前瞻性调查分析方法,收集浙江大学医学院附属儿童医院222例门诊再障患儿1611个全血稳态谷浓度样本,用NONMEM程序建立群体药物动力学模型,定量考察年龄、身高、体重、BSA、GFR、合并用药强的松、司坦唑醇等固定效应对药物动力学参数的影响。
结果
CsA稳态谷浓度药物动力学参数能用米-曼氏模型进行较好的拟合,用建模组获得的群体参数在验证组中有较理想的拟合优度。模型中最终保留了年龄、体表面积(BSA)、肾小球滤过率(GFR)、和司坦唑醇合并用药4个固定效应,米-曼氏模型参数V_m和K_m为206(mg/d)、39.9(μg/L),V_m和K_m的个体间变异分别是28.0%和67.7%,个体自身的变异为29.2%。
用全数据集模拟的最终模型为:DR=[206+9.64×(AGE-8.26)+225×(BSA-1.06)]×Exp(η_1)×Css/({[39.9+3.61×(GFR-1565)]×(1+0.868×STZ)}×Exp(η_2)+Css)+ε
结论
环孢素治疗儿童再障具有明显的年龄依赖性的药动学变化特征。用本研究所得到的群体药物动力学模型结合Bayesian反馈法可以为临床儿童血液病患儿CsA的个体化用药提供方法。
目的:
初步研究不同出生体重新生大鼠CYP3A1/2、PXR、CAR和HNF4α表达差异及其影响CYP3A1/2的调控因素。
方法:
怀孕第2天的SD孕鼠,随机分配入自由进食组(nourished rats;NR)和营养限制组(undernourished rats,UR),NR组母鼠所生仔鼠,且体重在5.2～7.2g之间的为正常出生体重组(normal birth weight group,NBW,n=15);UR组母鼠所生仔鼠且体重＜5.2g为低出生体重组(low birth weight group,LBW,n=15)。NR组母鼠所生仔鼠且体重＞7.2g的新生大鼠为HBW(High birth weight group,HBW,n=15)组。
Real-time RT-PCR方法测定CYP3A1/2、PXR、CAR和HNF4α肝组织mRNA表达。免疫组织化学方法检测CYP3A1/2,CAR和HNF4α蛋白表达和组织定位,对染色强度和阳性细胞数计分后评价蛋白表达差异。
结果
低出生体重显著影响了CYP3A2和CAR的mRNA表达以及CYP3A1和CAR的蛋白表达。而高出生体重显著影响了CYP3A2和HNF4α的mRNA水平,以及CYP3A1和HNF4α的蛋白表达水平。CYP3A1的mRNA与CYP3A2和HNF4α的mRNA的表达具有相关性。
结论
出生体重对CYP3A1/2以及核受体的表达具有不同程度的影响。提示,需注意不同出生体重新生儿对药物的反应性差异。
目的
研究不同发育阶段、高脂饮食状态下CYP3A1/2以及核受体的表达变化规律。探讨影响发育过程中CYP3A1/2表达调控的重要因素。
方法
LBW模型建立、mRNA和蛋白测定方法同本章第一节。
模型分组:
NBW-常规饲料组(normal birth weight-normal diet group,NN组)
NBW-高脂饲料组(normal birth weight-high lipid and high energy group,NH组)
LBW-常规饲料组(low birth weight-normal diet group,LN组)
LBW-高脂饲料组(loW birth weight-high lipid and high energy group,LH组)
以上各组大鼠分别在生后3、7、14、21、28、56和84天收集肝脏(n=6-8/组)。
结果
CYP3A1/2以及核蛋白PXR、CAR、HNF4α的表达具有年龄依赖性。低出生体重可以改变代谢酶和核受体表达并且一直持续到成年期,其中对PXR/CAR的改变尤为明显,而且在很大程度上与CYP3A1/2表达相关。高脂饮食可以改变代谢酶和核受体的表达,其中HNF4α基因表达的改变最为显著。
结论
发育过程中CYP3A以及相关核受体表达的改变和相互作用,会导致机体对物质代谢的变化,影响治疗药物的安全性和药物相互作用,临床上需关注低出生体重和肥胖患儿的合理用药。
Objectives
The aim of this study was to develop a population pharmacokinetic model of cyclosporin(CsA) in pediatric aplastic anemia patients,thereby optimizing its therapeutic effects in clinical trials.
Methods
We have prospectively collected 1611 routine samples of average steady-state CsA trough concentration in 222 pediatric patients with hematologic disease in a Chinese population.These data were analyzed using the nonlinear mixed-model program(NONMEM).Based on the influence of numerous tested covariates(i.e.,age, height,weight,BSA,GFR),a population pharmacokinetic model of CsA was developed and further validated by data splitting.
Results
After oral administration,the whole blood steady-state trough concentration of CsA could be well described by a Michaelis-Menten model,in which four covariates (i.e.,age,BSA,GFR,and stanozolol) were included.Furthermore,the Michaelis-Menten constants,Vm and Km with interindividual variation in parenthesis, were estimated to be 206 mg/d(28%) and 39.9μg/L(67.7%),respectively.The intraindividual variation of V_m and K_m was 29.2%.
The final model was described as: DR=([206+9.64×(AGE-8.26)+22.5×(BSA-1.06)]×Exp(η_1)×Css)/({[39.9+3.6l×(GFR-1565]×(1+0.868×STZ)}×Exp(η_2)+Css)+ε
Conclusions
In conclusion,pharrnacokinetic parameters of CsA in pediatric aplastic anemia patients may be largely influenced by age,BSA,GFR and Stanzolol.We propose that our CsA population pharrnaeokinetie model,combined with the Bayesian forecasting method,may optimize the dosage of CsA in clinical trials.
Objectives
The aim of this study was to investigate the effects of birth weight on the expression and regulation of CYP3A1/2 as well as its nuclear receptors,including PXR, CAR,and HNF4a in newborn rats.
Methods
Pregnant rats were randomly divided into two groups:nourished and under-nourished.The offspring of nourished rats with birth weight between 5.2～7.2g were defined as normal-birth-weight group(NBW,n=15),while those of undernourished rats with birth weight under 5.2g were defined as low-birth-weight group(LBW,n=15).Additionally,the offspring of nourished rats with birth weight above 7.2g were defined as high-birth-weight group(HBW,n=15).
Hepatic mRNA expression of CYP3A1,PXR.,CAR and HNF4αwas detected by quantitative real-time RT-PCR.Immunohistochemistry was performed to investigate the corresponding protein expression and localization.Protein expression was evaluated by using a score corresponding to the sum of both staining intensity and percentage of positive hepatocytes.
Results
Low birth weight could significantly affect mRNA expression of CYP3A2 and CAR,and protein expression of CYP3A1 and CAR.In contrast,the high birth weight could significant affect the mRNA levels of CYP3A2 and HNF4α,and also the protein levels of CYP3A1 and HNF4a expression.CYP3A1 mRNA expression correlated with that of CYP3A2 and HNF4a.
Conclusions
In conclusion,birth weight could influence the production of several drug metabolism enzymes(i.e.,CYP3A1/2,and its nuclear receptors) in newborn rats, which should be taken into consideration when delivering medication to LBW and HBW infants in humans.
Objectives
In this study,we have aimed to investigate the effects of low birth weight and high-lipid diet on the expression and regulation of CYP3A1/2 as well as its nuclear receptors,including PXR,CAR,and HNF4α,in female rats during development.
Methods
The LBW animal model was established as mentioned above in Part One.Gene expression analysis(mRNA and protein levels) was performed as described previously. According to different birth weight and diet feeding,rats were divided into 4 groups as following:
1.Normal birth weight-normal diet group,NN-group
2.Normal birth weight-high lipid and high energy group,NH-group
3.Low birth weight-normal diet group,LN-group
4.Low birth weight-high lipid and high energy group,LH-group
Livers were isolated from each group,and subsequently used for gene expression study (i.e.,mRNA and protein levels) at 3,7,14,21,28,56,84 days after birth(n=6-8 per group).
Results
The hepatic expression of CYP3A1/2 and its nuclear receptors(i.e.,PXR,CAR, and HNF4α) was found to be age'dependent in rats.The effects of low birth weight on the expression of CYP3A1/2,PXR,CAR and HNF4αcan persist after birth.In particular,the expression of PXR and CAR was dramatically altered under the LBW situation,which was correlated with the expression of CYP3A1/2.Furthermore,the expression of CYP3A1/2 and their nuclear receptors,especially the HNF4α,was largely influenced by the high-lipid diet feeding in rats.
Conclusion
In conclusion,the hepatic expression and modulation of CYP3A1/2 and its nuclear receptors(i.e.,PXR,CAR,and HNF4α) were influenced by both birth weight and high-lipid diet feeding in developing rats.We propose that the alteration and interaction of CYP3A and its nuclear receptors have potential clinical implications for optimal medication in low birth weigh and fat children.
引文
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34.Urquhart BL,Tirona RG,Kim RB.Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters:implications for interindividual variability in response to drugs.J Clin Pharmacol 2007 May;47(5):566-78.
35.Bell AW,Michalopoulos GK.Phenobarbital regulates nuclear expression of HNF-4alpha in mouse and rat hepatocytes independent of CAR and PXR.Hepatology(Baltimore,Md 2006 Jul;44(1):186-94.
36.Tirona RG,Lee W,Leake BF,et al.The orphan nuclear receptor HNF4alpha determines PXR-and CAR-mediated xenobiotic induction of CYP3A4.Nat Med 2003 Feb;9(2):220-4.
37.Greger DL,Philipona C,Blum JW.Ontogeny of mRNA abundance of nuclear receptors and nuclear receptor target genes in young cattle.Domest Anim Endocrinol 2006 Jul;31(1):76-87.
38.Balasubramaniyan N,Shahid M,Suchy FJ,et al.Multiple mechanisms of ontogenic regulation of nuclear receptors during rat liver development.Am J Physiol Gastrointest Liver Physiol 2005 Feb;288(2):G251-60.
39.Kamiya A,Inoue Y,Gonzalez FJ.Role of the hepatocyte nuclear factor 4alpha in control of the pregnane X receptor during fetal liver development.Hepatology 2003 Jun;37(6):1375-84.
40.Vyhlidal CA,Gaedigk R,Leeder JS.Nuclear receptor expression in fetal and pediatric liver:correlation with CYP3A expression.Drug Metab Dispos 2006 Jan;34(1):131-7.
41.胡亚美,江载芳.诸福棠实用儿科学.7 ed.北京:人民卫生出版社,2002.
42.Beardsall K,Diderholm BM,Dunger DB.Insulin and carbohydrate metabolism.Best practice &research 2008 Feb;22(1):41-55.
43.Zethelius B,Lithell H,Hales CN,et al.Insulin sensitivity,proinsulin and insulin as predictors of coronary heart disease.A population-based 10-year,follow-up study in 70-year old men using the euglycaemic insulin clamp.Diabetologia 2005 May;48(5):862-7.
44.Wells JC.The thrifty phenotype as an adaptive maternal effect.Biol Rev Camb Philos Soc 2007Feb;82(1):143-72.
45.Ahlsson FS,Diderholm B,Ewald U,et al.Lipolysis and insulin sensitivity at birth in infants who are large for gestational age.Pediatrics 2007 Nov;120(5):958-65.
46.Wang X,Liang L,Du L.The effects of intrauterine undernutrition on pancreas ghrelin and insulin expression in neonate rats.J Endocrinol 2007 Jul;194(1):121-9.
47.Evagelidou EN,Kiortsis DN,Bairaktari ET,et al.Lipid profile,glucose homeostasis,blood pressure,and obesity-anthropometric markers in macrosomic offspring of nondiabetic mothers.Diabetes care 2006 Jun;29(6):1197-201.
48.Sidhu JS,Omiecinski CJ.Insulin-mediated modulation of cytochrome P450 gene induction profiles in primary rat hepatocyte cultures.J Biochem Mol Toxicol 1999;13(1):1-9.
49.Haslam DN,James WP.Obesity.Lancet 2005 Oct 1;366(9492):1197-209.
50.Reilly JJ.Obesity in childhood and adolescence:evidence based clinical and public health perspectives.Postgraduate medical journal 2006 Jul;82(969):429-37.
51.武阳丰,马冠生,胡永华,李艳平,李贤,崔朝辉,陈春明,孔灵芝.中国居民的超重和肥胖流行现状.中华预防医学杂志 2005;39(5):316-20.
52.Barker DJ.Fetal origins of coronary heart disease.Br Heart J 1993 Mar;69(3):195-6.
53.Arantes VC,Teixeira VP,Reis MA,et ai.Expression of PDX-1 is reduced in pancreatic islets from pups of rat dams fed a low protein diet during gestation and lactation.The Journal of nutrition 2002Oct;132(10):3030-5.
54.Allegaert K,Anderson BJ,van den Anker JN,et al.Renal drug clearance in preterm neonates:relation to prenatal growth.Therapeutic drug monitoring 2007 Jun;29(3):284-91.
55.Frattarelli DA,Ergun H,Lulic-Botica M,et al.Vancomycin elimination in human infants with intrauterine growth retardation.The Pediatric infectious disease journal 2005 Nov;24(11):979-83.
56.Desai M,Crowther NJ,Lucas A,et al.Organ-selective growth in the offspring of protein-restricted mothers.The British journal of nutrition 1996 Oct;76(4):591-603.
57.Gagnon R.Placental insufficiency and its consequences.Eur J Obstet Gynecol Reprod Biol 2003Sep 22;110 Suppl 1:S99-107.
58.Jungermann K,Kietzmann T.Oxygen:modulator of metabolic zonation and disease of the liver.Hepatology 2000 Feb;31(2):255-60.
59. 成令忠,钟翠平,蔡文琴.现代组织学.1 ed. 上海:上海科技文献出版社 2003.
60. Johnson TN, Tanner MS, Tucker GT. A comparison of the ontogeny of enterocytic and hepatic cytochromes P450 3A in the rat. Biochem Pharmacol 2000 Dec l;60 (11): 1601-10.
61. Mahnke A, Strotkamp D, Roos PH, et al. Expression and inducibility of cytochrome P450 3A9 (CYP3A9) and other members of the CYP3A subfamily in rat liver. Arch Biochem Biophys 1997 Jan 1;337 (1): 62-8.
62. Huss JM, Wang SI, Kasper CB. Differential glucocorticoid responses of CYP3A23 and CYP3A2 are mediated by selective binding of orphan nuclear receptors. Archives of biochemistry and biophysics 1999 Dec 15;372(2): 321-32.
63. Kodama S, Koike C, Negishi M, et al. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Molecular and cellular biology 2004 Sep;24 (18): 7931-40.
64. Tien ES, Negishi M. Nuclear receptors CAR and PXR in the regulation of hepatic metabolism. Xenobiotica 2006 Oct-Nov;36 (10-11): 1152-63.
65. Kim SK, Novak RF. The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression. Pharmacol Ther 2007 Jan;113 (1): 88-120.
66. Parviz F, Matullo C, Garrison WD, et al. Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet 2003 Jul;34 (3): 292-6.
67. Timsit YE, Negishi M. CAR and PXR: the xenobiotic-sensing receptors. Steroids 2007 Mar;72 (3):231-46.
68. Echchgadda I, Song CS, Oh T, et al. The xenobiotic-sensing nuclear receptors pregnane X receptor,constitutive androstane receptor, and orphan nuclear receptor hepatocyte nuclear factor 4alpha in the regulation of human steroid-/bile acid-sulfotransferase. Mol Endocrinol 2007 Sep;21 (9): 2099-111.
69. Nakamura H, Hirai M, Ohmori S, et al. Changes in urinary 6beta-hydroxycortisol/cortisol ratio after birth in human neonates. Eur J Clin Pharmacol 1998 Jan;53 (5): 343-6.
70. Lesko SM, Mitchell AA. The safety of acetaminophen and ibuprofen among children younger than two years old. Pediatrics 1999 Oct;104 (4): e39.
71. Semama DS, Bernardini S, Louf S, et al. Effects of cisapride on QTc interval in term neonates. Arch Dis Child Fetal Neonatal Ed 2001 Jan;84 (1): F44-6.
72. Wang H, LeCluyse EL. Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin Pharmacokinet 2003;42 (15): 1331-57.
73. Blanco JG, Harrison PL, Evans WE, et al. Human cytochrome P450 maximal activities in pediatric versus adult liver. Drug Metab Dispos 2000 Apr;28 (4): 379-82.
74. Imaoka S, Terano Y, Funae Y. Constitutive testosterone 6 beta-hydroxylase in rat liver. Journal of biochemistry 1988 Sep;104 (3): 481-7.
75. Cooper ICO, Reik LM, Jayyosi Z, et al. Regulation of two members of the steroid-inducible cytochrome P450 subfamily (3A) in rats. Archives of biochemistry and biophysics 1993 Mar;301 (2):345-54.
76. Ginsberg G, Hattis D, Sonawane B. Incorporating pharmacokinetic differences between children and adults in assessing children's risks to environmental toxicants. Toxicol Appl Pharmacol 2004 Jul 15;198(2): 164-83.
77. Wauthier V, Verbeeck RK, Calderon PB. Decreased CYP3A2 expression and activity in senescent male Wistar rats: is there a role for HNF4alpha? Experimental gerontology 2006 Sep;41 (9): 846-54.
78. Kanamori M, Takahashi H, Echizen H. Developmental changes in the liver weight- and body weight-normalized clearance of theophylline, phenytoin and cyclosporine in children. Int J Clin Pharmacol Ther 2002 Nov;40 (11): 485-92.
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80. Jump DB, Clarke SD. Regulation of gene expression by dietary fat. Annual review of nutrition 1999;19: 63-90.
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84. Wu G, Bazer FW, Cudd TA, et al. Maternal nutrition and fetal development. J Nutr 2004 Sep;134(9): 2169-72.
85. Woodcroft KJ, Novak RF. Insulin differentially affects xenobiotic-enhanced, cytochrome P-450 (CYP)2E1, CYP2B, CYP3A, and CYP4A expression in primary cultured rat hepatocytes. J Pharmacol Exp Ther 1999 May;289 (2): 1121-7.
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32.Yoshinari K,Takagi S,Yoshimasa T,et al.Hepatic CYP3A expression is attenuated in obese mice fed a high-fat diet.Pharm Res 2006 Jun;23(6):1188-200.
33.Pascussi JM,Gerbal-Chaloin S,Duret C,et al.The Tangle of Nuclear Receptors that Controls Xenobiotic Metabolism and Transport:Crosstalk and Consequences.Annu Rev Pharmacol Toxicol 2008Feb 10;48:1-32.
34.Urquhart BL,Tirona RG,Kim RB.Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters:implications for interindividual variability in response to drugs.J Clin Pharmacol 2007 May;47(5):566-78.
35.Bell AW,Michalopoulos GK.Phenobarbital regulates nuclear expression of HNF-4alpha in mouse and rat hepatocytes independent of CAR and PXR.Hepatology(Baltimore,Md 2006 Jul;44(1):186-94.
36.Tirona RG,Lee W,Leake BF,et al.The orphan nuclear receptor HNF4alpha determines PXR-and CAR-mediated xenobiotic induction of CYP3A4.Nat Med 2003 Feb;9(2):220-4.
37.Greger DL,Philipona C,Blum JW.Ontogeny of mRNA abundance of nuclear receptors and nuclear receptor target genes in young cattle.Domest Anim Endocrinol 2006 Jul;31(1):76-87.
38.Balasubramaniyan N,Shahid M,Suchy FJ,et al.Multiple mechanisms of ontogenic regulation of nuclear receptors during rat liver development.Am J Physiol Gastrointest Liver Physiol 2005 Feb;288(2):G251-60.
39.Kamiya A,Inoue Y,Gonzalez FJ.Role of the hepatocyte nuclear factor 4alpha in control of the pregnane X receptor during fetal liver development.Hepatology 2003 Jun;37(6):1375-84.
40.Vyhlidal CA,Gaedigk R,Leeder JS.Nuclear receptor expression in fetal and pediatric liver:correlation with CYP3A expression.Drug Metab Dispos 2006 Jan;34(1):131-7.
41.胡亚美,江载芳.诸福棠实用儿科学.7 ed.北京:人民卫生出版社,2002.
42.Beardsall K,Diderholm BM,Dunger DB.Insulin and carbohydrate metabolism.Best practice &research 2008 Feb;22(1):41-55.
43.Zethelius B,Lithell H,Hales CN,et al.Insulin sensitivity,proinsulin and insulin as predictors of coronary heart disease.A population-based 10-year,follow-up study in 70-year old men using the euglycaemic insulin clamp.Diabetologia 2005 May;48(5):862-7.
44.Wells JC.The thrifty phenotype as an adaptive maternal effect.Biol Rev Camb Philos Soc 2007Feb;82(1):143-72.
45.Ahlsson FS,Diderholm B,Ewald U,et al.Lipolysis and insulin sensitivity at birth in infants who are large for gestational age.Pediatrics 2007 Nov;120(5):958-65.
46.Wang X,Liang L,Du L.The effects of intrauterine undernutrition on pancreas ghrelin and insulin expression in neonate rats.J Endocrinol 2007 Jul;194(1):121-9.
47.Evagelidou EN,Kiortsis DN,Bairaktari ET,et al.Lipid profile,glucose homeostasis,blood pressure,and obesity-anthropometric markers in macrosomic offspring of nondiabetic mothers.Diabetes care 2006 Jun;29(6):1197-201.
48.Sidhu JS,Omiecinski CJ.Insulin-mediated modulation of cytochrome P450 gene induction profiles in primary rat hepatocyte cultures.J Biochem Mol Toxicol 1999;13(1):1-9.
49.Haslam DN,James WP.Obesity.Lancet 2005 Oct 1;366(9492):1197-209.
50.Reilly JJ.Obesity in childhood and adolescence:evidence based clinical and public health perspectives.Postgraduate medical journal 2006 Jul;82(969):429-37.
51.武阳丰,马冠生,胡永华,李艳平,李贤,崔朝辉,陈春明,孔灵芝.中国居民的超重和肥胖流行现状.中华预防医学杂志 2005;39(5):316-20.
52.Barker DJ.Fetal origins of coronary heart disease.Br Heart J 1993 Mar;69(3):195-6.
53.Arantes VC,Teixeira VP,Reis MA,et ai.Expression of PDX-1 is reduced in pancreatic islets from pups of rat dams fed a low protein diet during gestation and lactation.The Journal of nutrition 2002Oct;132(10):3030-5.
54.Allegaert K,Anderson BJ,van den Anker JN,et al.Renal drug clearance in preterm neonates:relation to prenatal growth.Therapeutic drug monitoring 2007 Jun;29(3):284-91.
55.Frattarelli DA,Ergun H,Lulic-Botica M,et al.Vancomycin elimination in human infants with intrauterine growth retardation.The Pediatric infectious disease journal 2005 Nov;24(11):979-83.
56.Desai M,Crowther NJ,Lucas A,et al.Organ-selective growth in the offspring of protein-restricted mothers.The British journal of nutrition 1996 Oct;76(4):591-603.
57.Gagnon R.Placental insufficiency and its consequences.Eur J Obstet Gynecol Reprod Biol 2003Sep 22;110 Suppl 1:S99-107.
58.Jungermann K,Kietzmann T.Oxygen:modulator of metabolic zonation and disease of the liver.Hepatology 2000 Feb;31(2):255-60.
59. 成令忠,钟翠平,蔡文琴.现代组织学.1 ed. 上海:上海科技文献出版社 2003.
60. Johnson TN, Tanner MS, Tucker GT. A comparison of the ontogeny of enterocytic and hepatic cytochromes P450 3A in the rat. Biochem Pharmacol 2000 Dec l;60 (11): 1601-10.
61. Mahnke A, Strotkamp D, Roos PH, et al. Expression and inducibility of cytochrome P450 3A9 (CYP3A9) and other members of the CYP3A subfamily in rat liver. Arch Biochem Biophys 1997 Jan 1;337 (1): 62-8.
62. Huss JM, Wang SI, Kasper CB. Differential glucocorticoid responses of CYP3A23 and CYP3A2 are mediated by selective binding of orphan nuclear receptors. Archives of biochemistry and biophysics 1999 Dec 15;372(2): 321-32.
63. Kodama S, Koike C, Negishi M, et al. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug-metabolizing and gluconeogenic enzymes. Molecular and cellular biology 2004 Sep;24 (18): 7931-40.
64. Tien ES, Negishi M. Nuclear receptors CAR and PXR in the regulation of hepatic metabolism. Xenobiotica 2006 Oct-Nov;36 (10-11): 1152-63.
65. Kim SK, Novak RF. The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression. Pharmacol Ther 2007 Jan;113 (1): 88-120.
66. Parviz F, Matullo C, Garrison WD, et al. Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet 2003 Jul;34 (3): 292-6.
67. Timsit YE, Negishi M. CAR and PXR: the xenobiotic-sensing receptors. Steroids 2007 Mar;72 (3):231-46.
68. Echchgadda I, Song CS, Oh T, et al. The xenobiotic-sensing nuclear receptors pregnane X receptor,constitutive androstane receptor, and orphan nuclear receptor hepatocyte nuclear factor 4alpha in the regulation of human steroid-/bile acid-sulfotransferase. Mol Endocrinol 2007 Sep;21 (9): 2099-111.
69. Nakamura H, Hirai M, Ohmori S, et al. Changes in urinary 6beta-hydroxycortisol/cortisol ratio after birth in human neonates. Eur J Clin Pharmacol 1998 Jan;53 (5): 343-6.
70. Lesko SM, Mitchell AA. The safety of acetaminophen and ibuprofen among children younger than two years old. Pediatrics 1999 Oct;104 (4): e39.
71. Semama DS, Bernardini S, Louf S, et al. Effects of cisapride on QTc interval in term neonates. Arch Dis Child Fetal Neonatal Ed 2001 Jan;84 (1): F44-6.
72. Wang H, LeCluyse EL. Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin Pharmacokinet 2003;42 (15): 1331-57.
73. Blanco JG, Harrison PL, Evans WE, et al. Human cytochrome P450 maximal activities in pediatric versus adult liver. Drug Metab Dispos 2000 Apr;28 (4): 379-82.
74. Imaoka S, Terano Y, Funae Y. Constitutive testosterone 6 beta-hydroxylase in rat liver. Journal of biochemistry 1988 Sep;104 (3): 481-7.
75. Cooper ICO, Reik LM, Jayyosi Z, et al. Regulation of two members of the steroid-inducible cytochrome P450 subfamily (3A) in rats. Archives of biochemistry and biophysics 1993 Mar;301 (2):345-54.
76. Ginsberg G, Hattis D, Sonawane B. Incorporating pharmacokinetic differences between children and adults in assessing children's risks to environmental toxicants. Toxicol Appl Pharmacol 2004 Jul 15;198(2): 164-83.
77. Wauthier V, Verbeeck RK, Calderon PB. Decreased CYP3A2 expression and activity in senescent male Wistar rats: is there a role for HNF4alpha? Experimental gerontology 2006 Sep;41 (9): 846-54.
78. Kanamori M, Takahashi H, Echizen H. Developmental changes in the liver weight- and body weight-normalized clearance of theophylline, phenytoin and cyclosporine in children. Int J Clin Pharmacol Ther 2002 Nov;40 (11): 485-92.
79. Omiecinski CJ, Hassett C, Costa P. Developmental expression and in situ localization of the phenobarbital-inducible rat hepatic mRNAs for cytochromes CYP2B1, CYP2B2, CYP2C6, and CYP3A1. Mol Pharmacol 1990 Oct;38 (4): 462-70.
80. Jump DB, Clarke SD. Regulation of gene expression by dietary fat. Annual review of nutrition 1999;19: 63-90.
81. Buhler R, Lindros KO, Nordling A, et al. Zonation of cytochrome P450 isozyme expression and induction in rat liver. Eur J Biochem 1992 Feb 15;204 (1): 407-12.
82. Wright MC, Edwards RJ, Pimenta M, et al. Developmental changes in the constitutive and inducible expression of cytochrome P450 3A2. Biochem Pharmacol 1997 Oct 1;4 (7): 841-6.
83. Ribeiro V LM. Cloning and characterization of a novel CYP3A1 allelic variant: analysis of CYP3A1 and CYP3A2 sex-hormone-dependent expression reveals that the CYP3A2 gene is regulated by testosterone. Arch Biochem Biophys 1992 Feb 14:;293 (1): 147-52.
84. Wu G, Bazer FW, Cudd TA, et al. Maternal nutrition and fetal development. J Nutr 2004 Sep;134(9): 2169-72.
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