药物代谢酶的基因多态性对肝移植后他克莫司用药的影响
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摘要
目的：通过不同灌注方法的比较,探讨原位肝移植中经下腔静脉逆行灌注对大鼠移植肝缺血再灌注损伤的影响。
方法：成功建立54例大鼠肝移植模型,并随机分为三组,每组18例。第一组门静脉组,即经门静脉顺行灌注；第二组肝动脉+门静脉组,即同时开放肝动脉及门静脉顺行灌注；第三组下腔静脉组,即先吻合下腔静脉后开放逆行灌注,然后吻合门静脉及肝动脉。分别检测肝移植术后1h、6h及24h的血清谷草转氨酶、血清谷丙转氨酶、移植肝组织病理变化及肝细胞凋亡指数。
结果：第三组逆行灌注组的血清转氨酶、血清谷丙转氨酶水平明显低于第一、二两组的顺行灌注组,其中第二组肝动脉+门静脉组酶学水平最高；移植肝的病理损伤情况第二组最重,第一组次之,第三组最轻；肝细胞凋亡指数第二组>第一组>第三组。
结论：移植肝的缺血再灌注损伤与灌注方法有关；与传统的顺行灌注相比,经下腔静脉逆灌注可以减轻移植肝的缺血再灌注损伤。
目的：通过观察不同组别中血清谷丙转氨酶、血清胆红素及肝组织排斥反应的程度,探讨CYP3AmRNA的表达在肝移植大鼠的他克莫司血药浓度中的意义,进而评估其在他克莫司免疫抑制中的作用。
方法：建立SD-Wistar大鼠肝移植急性排斥反应模型72例,同时随机分为空白对照组、实验组、肝酶诱导组及肝酶抑制组四组,分别于肝移植术后1d、4d、7d三个时间点分批处死取材,抽血检测血清谷丙转氨酶、胆红素及他克莫司的血药浓度,光镜下观察肝组织病理学变化,并检测肝组织中CYP3AmRNA的表达情况。
结果：空白对照组中18对大鼠成功建立16对急性排斥反应模型,成功率为88.9%；血清谷丙转氨酶及胆红素,空白对照组依次高于肝酶诱导组、实验组及肝酶抑制组,与光镜下肝组织的病变程度一致；他克莫司的血药浓度,肝酶抑制组最高,依次为实验组、肝酶诱导组,空白对照组最低；而肝组织中CYP3AmRNA的表达量,肝酶诱导组最高,其次为空白对照组和实验组,肝酶抑制组最低。
结论：使用SD-Wistar大鼠的肝移植,可以成功稳定的建立大鼠肝移植的急性排斥反应模型；肝组织中CYP3AmRNA的表达量会影响他克莫司的血药浓度,进而影响其免疫抑制的作用；他克莫司既是CYP3A酶的底物,可能又是CYP3A酶的抑制剂。
目的：
1.总结肝移植术后免疫抑制剂他克莫司用量及其血药浓度的个体化差异的特点；
2.研究肝移植人群中CYP3A5和ABCBl基因多态性分布的特点；
3.探讨肝移植术后他克莫司用量及其血药浓度的个体化差异与CYP3A5和ABCBl基因多态性的关系。
方法：
1.统计我院67例肝移植病人的病历资料,监测肝移植患者术后不同时间的他克莫司的用量(D)、血药浓度(C)及校正后的C/D比值；
2.利用DNA直接测序检测所有肝移植受体CYP3A5和ABCBl的基因型；
3.67例肝移植病人,于移植后按照目标血药浓度一天分两次给予口服他克莫司,并根据血药浓度不断调整剂量,以达到目标血药浓度(7-10ng/m1),分为术后1周、2周及1月三组。
结果：
1.肝移植术后他克莫司的口服需药量在个体间存在很大差异,校正后的C/D值也存在很大差异；
2.67例肝移植患者中,CYP3A5*1/*1基因型有15例、CYP3A5*1/*3基因型有23例、CYP3A5*3/*3基因型有29例,发生频率分别为22.4%、34.3%、43.3%。相比CYP3A5*1/*1基因型和CYP3A5*1/*3基因型两组,CYP3A5*3/*3组他克莫司的需药量最低,而校正后的C/D比值最高。
3.67例肝移植患者中,ABCBl不同位点的基因多态性分布不同,其中仅ABCBl3435C>T基因多态性与他克莫司用量有关。ABCBl3435>T C/C基因型22例、C/T基因型40例、T/T基因型5例,发生频率分别为32.8%、59.7%、7.5%。
结论：
1.肝移植患者术后免疫抑制剂他克莫司的治疗用量存在很大的个体化差异；
2.CYP3A5和ABCBl的基因多态性可能是肝移植患者术后他克莫司药代动力学显著个体差异的重要因素；
3.CYP3A5非表达型(*3/*3)较表达型(*1/*1、*1/*3)基因型的患者需要更低剂量的他克莫司便可达到目标血药浓度水平,ABCBl3435C>T低表达组(C/T、T/T)较高表达组(C/C)需要更低剂量的他克莫司便可达到目标血药浓度水平；
4.检测CYP3A5和ABCBl的基因多态性可以优化肝移植患者他克莫司个体化治疗的方案。
Part I
The experimental study of liver graft injury by ischemia and reperfusion secondary to retrograde reperfusion
Aim:The aim of this study was to evaluate the influence of retrograde reperfusion via the vena cava on ischemic/reperfusion injury (I/R-injury) in a rat liver transplantation model, under comparing different kinds of reperfusion.
Methods:Fifty four orthoptic rat liver transplantations were performed on male SD rats. Three groups (n=18) were formed. Group I:Antegrade reperfusion via the portal vein. Group II:Antegrade reperfusion, simultaneously, via the portal vein and the hepatic artery. Group III:Retrograde reperfusion via the vena cava. Serum parameters were determined one,6and24h after operation. Furthermore, the liver was taken for histological assessment. The early cell apoptosis index was examined also.
Results:Rats of group III showed significantly lower aspartate amino transferase and alanine aminotransferase serum levels compared with group I and group II rats. Aspartate amino transferase and alanine aminotransferase serum level were significantly lower in group I than in group II. In histology, group III livers showed significantly less leukocytic infiltrate than group I and group II livers, however, group II livers showed the most serious. The apoptosis index in the group III livers were lower than in the group I and group II livers.
Conclusions:Our data suggested that the expression of I/R-injury correlates with the type of reperfusion. Furthermore, this study was able to demonstrate that in a rat model, the retrograde reperfusion leads to a lower expression of I/R-injury than the antegrade reperfusion.
Objectives:According to the serum alanine transarninase, serum total bilirubin and the characteristics of the acute rejection in hepatic tissue, to investigate the significance of CYP3A mRNA expression in rat's blood concentration of tacrolimus following liver transplantation and immunosuppressive effect of tacrolimus.
Methods:With Sprague-Dawley rats as donors and male Wistar rats as recipients, seventy two acute rejection models of orthotopic liver transplantation in the rat were established. Recipients were divided into4groups:blank control group, experimental group, enzyme inhibition group and enzyme induction group. Every six recipients were sacrificed respectively at day1,4,7after OLT to detect the changes of serum alanine transarninase, serum total bilirubin, tacrolimus whole-blood trough concentrations and the grafts histology. CYP3A mRNA levels in rat hepatic tissue were determined by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR).
Results:The success rate of acute rejection model of orthotopic liver transplantation in blank control group was88.9%(16/18). Rats of blank control group showed the highest levels of serum alanine transarninase, serum total bilirubin and the histological score of the acute rejection in hepatic tissue compared with other three groups, however, rats of enzyme inhibition group showed the lowest levels, enzyme induction group was higher than experimental group. The blood drug level of tacrolimus in rats of enzyme inhibition group was the highest compared with other three groups, however, blank control group showed the lowest, enzyme induction group was lower than experimental group. CYP3A mRNA levels in hepatic tissue of enzyme induction group showed the highest compared with other three groups, however, enzyme inhibition group showed the lowest, blank control group was higher than experimental group.
Conclusions:Acute rejection experimental model of liver transplantation in rat could be stably established using SD rat as donor and Wistar rat as recipient. The expression of CYP3A mRNA levels in hepatic tissue may influence the tacrolimus whole-blood trough concentration and immunosuppressive effect of tacrolimus furthermore.
Objectives:
1. To summarize the clinical data in considerable interindividual differences of tacrolimus dosage and trough blood concentration during the early period after liver transplantation in patients.
2. To evaluate the distribution characteristics of CYP3A5and ABCB1gene polymorphisms in Chinese liver transplantation recipients.
3. To investigate the possible association of the ABCBl gene C3435T polymorphism and the CYP3A5gene A6986G polymorphism with tacrolimus trough concentration and dose requirements during the early period after liver transplantation in patients.
Methods:
1. The clinical data of sixty seven liver transplantation recipients were analyzed and tacrolimus whole-blood trough concentrations were measured by enzyme-linked immunospecific assay. Dose requirements and dose-adjusted trough concentrations (concentration/dose [C/D] ratios) were analyzed.
2. CYP3A5and ABCBl genotyping were performed by direct DNA sequencing using the polymerase chain reaction restriction sites polymorphism-based procedure.
3. Tacrolimus was administered twice daily at specified times post-transplant period according to the trough-targeting strategy. Sixty recipients with stable graft function were studied beyond1-month post transplantation. Whole blood samples were collected lw,2w and lm after both the morning and evening doses during hospitalization.
Results
1. Tacrolimus dose requirements and dose-adjusted trough concentrations (concentration/dose [C/D] ratios) after liver transplantation had great variation between individuals.
2. The CYP3A5*1/*1was observed in15subjects (22.4%),23(34.3%) carried*l/*3, and29(43.3%) carried*3/*3. CYP3A5*3/*3variant was associated with significant lower tacrolimus dose at lw,2w and lm compared with patients who did not (CYP3A5*3/*3) after transplantation. The tacrolimus C/D ratios were obviously higher in recipients carrying CYP3A5*3/*3.
3. A synonymous single nucleotide polymorphism (SNP) of ABCBl in various exon was different. Furthermore, ABCBl3435C>T polymorphisms was significantly correlated with tacrolimus dose-adjusted pre-dose concentrations at various time points. The ABCB13435C/C was observed in22subjects (32.8%), whereas40(59.7%) carried3435C/T and5(7.5%) carried3435T/T.
Conclusions
1. Tacrolimus dose requirement is characterized by a large interindividual variability requiring the use of therapeutic drug monitoring in daily clinical practice.
2. The present study shows that genetic polymorphisms in CYP3A5and ABCB1may be responsible, in part, for the large interindividual variability of tacrolimus pharmacokinetics during the early period after liver transplantation in patients.
3. Patients in CYP3A5non-expressors require a low dose of tacrolimus to reach target levels compared with expressors. Patients in ABCB1low-expressors require a low dose of tacrolimus to reach target levels compared with high-expressors.
4. In the future, genotyping patients for CYP3A5and ABCB1polymorphisms may help to optimize the tacrolimus individualized immunosuppressive therapy in liver transplantation.
方法：成功建立54例大鼠肝移植模型,并随机分为三组,每组18例。第一组门静脉组,即经门静脉顺行灌注；第二组肝动脉+门静脉组,即同时开放肝动脉及门静脉顺行灌注；第三组下腔静脉组,即先吻合下腔静脉后开放逆行灌注,然后吻合门静脉及肝动脉。分别检测肝移植术后1h、6h及24h的血清谷草转氨酶、血清谷丙转氨酶、移植肝组织病理变化及肝细胞凋亡指数。
结果：第三组逆行灌注组的血清转氨酶、血清谷丙转氨酶水平明显低于第一、二两组的顺行灌注组,其中第二组肝动脉+门静脉组酶学水平最高；移植肝的病理损伤情况第二组最重,第一组次之,第三组最轻；肝细胞凋亡指数第二组>第一组>第三组。
结论：移植肝的缺血再灌注损伤与灌注方法有关；与传统的顺行灌注相比,经下腔静脉逆灌注可以减轻移植肝的缺血再灌注损伤。
目的：通过观察不同组别中血清谷丙转氨酶、血清胆红素及肝组织排斥反应的程度,探讨CYP3AmRNA的表达在肝移植大鼠的他克莫司血药浓度中的意义,进而评估其在他克莫司免疫抑制中的作用。
方法：建立SD-Wistar大鼠肝移植急性排斥反应模型72例,同时随机分为空白对照组、实验组、肝酶诱导组及肝酶抑制组四组,分别于肝移植术后1d、4d、7d三个时间点分批处死取材,抽血检测血清谷丙转氨酶、胆红素及他克莫司的血药浓度,光镜下观察肝组织病理学变化,并检测肝组织中CYP3AmRNA的表达情况。
结果：空白对照组中18对大鼠成功建立16对急性排斥反应模型,成功率为88.9%；血清谷丙转氨酶及胆红素,空白对照组依次高于肝酶诱导组、实验组及肝酶抑制组,与光镜下肝组织的病变程度一致；他克莫司的血药浓度,肝酶抑制组最高,依次为实验组、肝酶诱导组,空白对照组最低；而肝组织中CYP3AmRNA的表达量,肝酶诱导组最高,其次为空白对照组和实验组,肝酶抑制组最低。
结论：使用SD-Wistar大鼠的肝移植,可以成功稳定的建立大鼠肝移植的急性排斥反应模型；肝组织中CYP3AmRNA的表达量会影响他克莫司的血药浓度,进而影响其免疫抑制的作用；他克莫司既是CYP3A酶的底物,可能又是CYP3A酶的抑制剂。
目的：
1.总结肝移植术后免疫抑制剂他克莫司用量及其血药浓度的个体化差异的特点；
2.研究肝移植人群中CYP3A5和ABCBl基因多态性分布的特点；
3.探讨肝移植术后他克莫司用量及其血药浓度的个体化差异与CYP3A5和ABCBl基因多态性的关系。
方法：
1.统计我院67例肝移植病人的病历资料,监测肝移植患者术后不同时间的他克莫司的用量(D)、血药浓度(C)及校正后的C/D比值；
2.利用DNA直接测序检测所有肝移植受体CYP3A5和ABCBl的基因型；
3.67例肝移植病人,于移植后按照目标血药浓度一天分两次给予口服他克莫司,并根据血药浓度不断调整剂量,以达到目标血药浓度(7-10ng/m1),分为术后1周、2周及1月三组。
结果：
1.肝移植术后他克莫司的口服需药量在个体间存在很大差异,校正后的C/D值也存在很大差异；
2.67例肝移植患者中,CYP3A5*1/*1基因型有15例、CYP3A5*1/*3基因型有23例、CYP3A5*3/*3基因型有29例,发生频率分别为22.4%、34.3%、43.3%。相比CYP3A5*1/*1基因型和CYP3A5*1/*3基因型两组,CYP3A5*3/*3组他克莫司的需药量最低,而校正后的C/D比值最高。
3.67例肝移植患者中,ABCBl不同位点的基因多态性分布不同,其中仅ABCBl3435C>T基因多态性与他克莫司用量有关。ABCBl3435>T C/C基因型22例、C/T基因型40例、T/T基因型5例,发生频率分别为32.8%、59.7%、7.5%。
结论：
1.肝移植患者术后免疫抑制剂他克莫司的治疗用量存在很大的个体化差异；
2.CYP3A5和ABCBl的基因多态性可能是肝移植患者术后他克莫司药代动力学显著个体差异的重要因素；
3.CYP3A5非表达型(*3/*3)较表达型(*1/*1、*1/*3)基因型的患者需要更低剂量的他克莫司便可达到目标血药浓度水平,ABCBl3435C>T低表达组(C/T、T/T)较高表达组(C/C)需要更低剂量的他克莫司便可达到目标血药浓度水平；
4.检测CYP3A5和ABCBl的基因多态性可以优化肝移植患者他克莫司个体化治疗的方案。
Part I
The experimental study of liver graft injury by ischemia and reperfusion secondary to retrograde reperfusion
Aim:The aim of this study was to evaluate the influence of retrograde reperfusion via the vena cava on ischemic/reperfusion injury (I/R-injury) in a rat liver transplantation model, under comparing different kinds of reperfusion.
Methods:Fifty four orthoptic rat liver transplantations were performed on male SD rats. Three groups (n=18) were formed. Group I:Antegrade reperfusion via the portal vein. Group II:Antegrade reperfusion, simultaneously, via the portal vein and the hepatic artery. Group III:Retrograde reperfusion via the vena cava. Serum parameters were determined one,6and24h after operation. Furthermore, the liver was taken for histological assessment. The early cell apoptosis index was examined also.
Results:Rats of group III showed significantly lower aspartate amino transferase and alanine aminotransferase serum levels compared with group I and group II rats. Aspartate amino transferase and alanine aminotransferase serum level were significantly lower in group I than in group II. In histology, group III livers showed significantly less leukocytic infiltrate than group I and group II livers, however, group II livers showed the most serious. The apoptosis index in the group III livers were lower than in the group I and group II livers.
Conclusions:Our data suggested that the expression of I/R-injury correlates with the type of reperfusion. Furthermore, this study was able to demonstrate that in a rat model, the retrograde reperfusion leads to a lower expression of I/R-injury than the antegrade reperfusion.
Objectives:According to the serum alanine transarninase, serum total bilirubin and the characteristics of the acute rejection in hepatic tissue, to investigate the significance of CYP3A mRNA expression in rat's blood concentration of tacrolimus following liver transplantation and immunosuppressive effect of tacrolimus.
Methods:With Sprague-Dawley rats as donors and male Wistar rats as recipients, seventy two acute rejection models of orthotopic liver transplantation in the rat were established. Recipients were divided into4groups:blank control group, experimental group, enzyme inhibition group and enzyme induction group. Every six recipients were sacrificed respectively at day1,4,7after OLT to detect the changes of serum alanine transarninase, serum total bilirubin, tacrolimus whole-blood trough concentrations and the grafts histology. CYP3A mRNA levels in rat hepatic tissue were determined by quantitative real-time reverse transcription polymerase chain reaction (RT-PCR).
Results:The success rate of acute rejection model of orthotopic liver transplantation in blank control group was88.9%(16/18). Rats of blank control group showed the highest levels of serum alanine transarninase, serum total bilirubin and the histological score of the acute rejection in hepatic tissue compared with other three groups, however, rats of enzyme inhibition group showed the lowest levels, enzyme induction group was higher than experimental group. The blood drug level of tacrolimus in rats of enzyme inhibition group was the highest compared with other three groups, however, blank control group showed the lowest, enzyme induction group was lower than experimental group. CYP3A mRNA levels in hepatic tissue of enzyme induction group showed the highest compared with other three groups, however, enzyme inhibition group showed the lowest, blank control group was higher than experimental group.
Conclusions:Acute rejection experimental model of liver transplantation in rat could be stably established using SD rat as donor and Wistar rat as recipient. The expression of CYP3A mRNA levels in hepatic tissue may influence the tacrolimus whole-blood trough concentration and immunosuppressive effect of tacrolimus furthermore.
Objectives:
1. To summarize the clinical data in considerable interindividual differences of tacrolimus dosage and trough blood concentration during the early period after liver transplantation in patients.
2. To evaluate the distribution characteristics of CYP3A5and ABCB1gene polymorphisms in Chinese liver transplantation recipients.
3. To investigate the possible association of the ABCBl gene C3435T polymorphism and the CYP3A5gene A6986G polymorphism with tacrolimus trough concentration and dose requirements during the early period after liver transplantation in patients.
Methods:
1. The clinical data of sixty seven liver transplantation recipients were analyzed and tacrolimus whole-blood trough concentrations were measured by enzyme-linked immunospecific assay. Dose requirements and dose-adjusted trough concentrations (concentration/dose [C/D] ratios) were analyzed.
2. CYP3A5and ABCBl genotyping were performed by direct DNA sequencing using the polymerase chain reaction restriction sites polymorphism-based procedure.
3. Tacrolimus was administered twice daily at specified times post-transplant period according to the trough-targeting strategy. Sixty recipients with stable graft function were studied beyond1-month post transplantation. Whole blood samples were collected lw,2w and lm after both the morning and evening doses during hospitalization.
Results
1. Tacrolimus dose requirements and dose-adjusted trough concentrations (concentration/dose [C/D] ratios) after liver transplantation had great variation between individuals.
2. The CYP3A5*1/*1was observed in15subjects (22.4%),23(34.3%) carried*l/*3, and29(43.3%) carried*3/*3. CYP3A5*3/*3variant was associated with significant lower tacrolimus dose at lw,2w and lm compared with patients who did not (CYP3A5*3/*3) after transplantation. The tacrolimus C/D ratios were obviously higher in recipients carrying CYP3A5*3/*3.
3. A synonymous single nucleotide polymorphism (SNP) of ABCBl in various exon was different. Furthermore, ABCBl3435C>T polymorphisms was significantly correlated with tacrolimus dose-adjusted pre-dose concentrations at various time points. The ABCB13435C/C was observed in22subjects (32.8%), whereas40(59.7%) carried3435C/T and5(7.5%) carried3435T/T.
Conclusions
1. Tacrolimus dose requirement is characterized by a large interindividual variability requiring the use of therapeutic drug monitoring in daily clinical practice.
2. The present study shows that genetic polymorphisms in CYP3A5and ABCB1may be responsible, in part, for the large interindividual variability of tacrolimus pharmacokinetics during the early period after liver transplantation in patients.
3. Patients in CYP3A5non-expressors require a low dose of tacrolimus to reach target levels compared with expressors. Patients in ABCB1low-expressors require a low dose of tacrolimus to reach target levels compared with high-expressors.
4. In the future, genotyping patients for CYP3A5and ABCB1polymorphisms may help to optimize the tacrolimus individualized immunosuppressive therapy in liver transplantation.
引文
[I]Merion RM. Current status and future of liver transplantation. Semin Liver Dis, 2010, 30(4): 411-421
[2]Marudanayagam R, Shanmugam V, Sandhu B, et al. Liver retransplantation in adults:a single-centre, 25-year experience. HPB (Oxford), 2010, 12(3): 217-224
[3]Tan HH, Martin P. Management of end-stage liver disease in chronic hepatitis B. Clin Liver Dis,2010,14(3):477-493
[4]Movahedi Z, Holt CD, Saab S. Liver transplant: a primer. Exp Clin Transplant, 2010, 8(2): 83-90
[5]Miyazaki ET, Dos Santos R Jr, Miyazaki MC, et al. Patients on the waiting list for liver transplantation: caregiver burden and stress. Liver Transpl, 2010, 16(10):1164-1168
[6]Kuriyama N, Isaji S, Hamada T, et al. Activated protein C prevents hepatic ischaemia-reperfusion injury in rats. Liver Int, 2009, 29(2):299-307
[7]Junnarkar SP, Tapuria N, Dutt N, et al. Bucillamine improves hepatic microcirculation and reduces hepatocellular injury after liver warm ischaemia-reperfusion injury. HPB (Oxford), 2009,11(3):264-273
[8]Hilmi IA, Peng Z, Planinsic RM, et al. N-acetylcysteine does not prevent hepatorenal ischaemia-reperfusion injury in patients undergoing orthotopic liver transplantation. Nephrol Dial Transplant, 2010, 25(7):2328-2333
[9]Andreani P, Hoti E, de la Serna S, et al. Ischaemic preconditioning of the graft in adult living related right lobe liver transplantation: impact on ischaemia-reperfusion injury and clinical relevance. HPB (Oxford), 2010, 12(7):439-446
[10]Jegatheeswaran S, Siriwardena AK. Experimental and clinical evidence for modification of hepatic ischaemia-reperfusion injury by N-acetylcysteine during major liver surgery. HPB (Oxford),2011,13(3):71-78
[11]Martins PN, Chang S, Mahadevapa B, et al. Liver grafts from selected older donors do not have significantly more ischaemia reperfusion injury. HPB (Oxford), 2011,13(3):212-220
[12]Suzuki S, Toledo-Pereyra LH, Rodriguez FJ, et al. Neutrophil infiltration as an important factor in liver ischemia and reperfusion injury. Modulating effects of FK506 and cyclosporine. Transplantation, 1993,55(6):1265-1272.
[13]Lee S, Charters AC, Chandler JG, et al. A technique for orthotopic liver transplantation in the rat. Transplantation, 1973,16(6):664-669
[14]Kamada N, Calne RY. A surgical experience with five hundred thirty liver transplants in the rat. Surgery, 1983,93(1 pt 1):64-69
[15]Miyata M, Fischer JH, Fuhs M, et al. A simple method for orthotopic liver transplantation in the rat. Cuff technique for three vascular anastomoses. Transplantation, 1980, 30(5): 335-338
[16]刘静,陈福,陈达丰等.改良双袖套法大鼠原位肝移植500例.世界华人消化杂志,2008,16(22)：2521-2524
[17]Matevossian E, Doll D, Huser N, et al. Liver transplantation in the rat: single-center experience with technique, long-ienn survival, and functional and histolugic findings. Transplant Proc, 2009, 41(6): 2631-2636
[18]Hang HL, Qiu YD, Zhu XH, et al. A novel model for external biliary drainage in rat orthotopic liver transplantation. Int J Artif Organs, 2008, 31(12): 1055-1058
[19]Glanemann M, Gaebelein G, Nussler N, et al. Transplantation of monocyte-derived hepatocyte-like cells (NeoHeps) improves survival in a model of acute liver failure. Ann Surg, 2009,249(1):149-154
[20]Ariyakhagom V, Schmitz V, Olschewski P, et al. Improvement of microsurgical techniques in orthotopic rat liver transplantation. J Surg Res, 2009, 153(2): 332-339
[21]Oldani G, Maestri M, Gaspari A, et al. A novel technique for rat liver transplantation using Quick Linker system: a preliminary result. J Surg Res, 2008, 149(2):303-309
[22]Seppen J, Filali EE, Elferink RO. Small animal models of hepatocyte transplantation. Methods Mol Biol,2009,481(8):75-82
[23]刘其雨,程若川,苏艳军等.双套管法制作大鼠胰十二指肠移植模型.中国普外基础与临床杂志,2007,14(4)：420-422
[24]Carpenter AJ, Follette DM, Sheppard B, et al. Simultaneous antegrade and retrograde reperfusion after cardioplegic arrest for coronary artery bypass. J Card Surg, 1999, 14(5): 354-358
[25]Kertsman VP, Kambarov SU, Mishra YK, et al. Antegrade and retrograde cardioplegia with different reperfusion techniques in patients with multiple coronary artery lesions. Indian Heart J,1992,44(2):103-107
[26]Matevossian E, Doll D, Huser N, et al. Liver transplantation in the rat: single-center experience with technique, long-term survival, and functional and histologic findings. Transplant Proc, 2009, 41(6): 2631-2636
[27]Heidenhain C, Heise M, Jonas S, et al. Retrograde reperfusion via vena cava lowers the risk of initial nonfunction but increases the risk of ischemic-type biliary lesions in liver transplantation-a randomized clinical trial. Transpl Int, 2006, 19(9):738-748
[28]Daniela K, Michael Z, Florian I, et al. Influence of retrograde flushing via the caval vein on the post-reperfusion syndrome in liver transplantation. Clin Transplant, 2004, 18(6):638-641
[29]Chen J, Singhapricha T, Hu KQ, et al. Postliver transplant acute renal injury and failure by the RIFLE criteria in patients with normal pretransplant serum creatinine concentrations:a matched study. Transplantation, 2011,91(3):348-353
[30]Kern H, Bald C, Brill T, et al. The influence of retrograde reperfusion on the ischaemia-/reperfusion injury after liver transplantation in the rat. Int J Exp Pathol, 2008, 89(6):433-437
[1]Castroagudin JF, Molina E, Varo E. Calcineurin inhibitors in liver transplantation: to be or not to be. Transplant Proc, 2011,43(6): 2220-2223
[2]Kelly D. Safety and efficacy of tacrolimus in pediatric liver recipients. Pediatr Transplant, 2011,15(1):19-24
[3]O'Leary JG, Trotter JF, Neri MA, et al. Effect of tacrolimus on survival in hepatitis C-infected patients after liver transplantation. Proc (Bayl Univ Med Cent), 2011,24(3):187-191
[4]Perez MJ, Garcia DM, Taybi BJ, et al. Cardiovascular risk factors after liver transplantation: analysis of related factors. Transplant Proc, 2011,43(3):739-741
[5]Masood MQ, Rabbani M, Jafri W, et al. Diabetic ketoacidosis associated with tacrolimus in solid organ transplant recipients. J Pak Med Assoc, 2011,61(3):288-290
[6]Koh T, Baek SH, Han JI, et al. Maculopathy associated with tacrolimus (FK 506). Korean J Ophthalmol, 2011,25(1):69-71
[7]Zhang HL. Tacrolimus leukoencephalopathy-is it posterior reversible encephalopathy syndrome? Pediatr Neurol, 2011,44(3):236
[8]Garces G, Contreras G, Carvalho D, et al. Chronic kidney disease after orthotopic liver transplantation in recipients receiving tacrolimus. Clin Nephrol, 2011,75(2): 150-157
[9]Metalidis C, Lerut E, Naesens M, et al. Expression of CYP3A5 and P-glycoprotein in renal allografts with histological signs of calcineurin inhibitor nephrotoxicity. Transplantation, 2011,91(10):1098-1102
[10]Herrero MJ, Sanchez-Plumed J, Galiana M, et al. Influence of pharmacogenetic polymorphisms in routine immunosuppression therapy after renal transplantation. Transplant Proc,2010,42(8):3134-3136
[11]Lampen A, Christians U, Guengerich FP, et al. Metabolism of the immunosuppressant tacrolimus in the small intestine: cytochrome P450, drug interactions, and interindividual variability. Drug Metab Dispos, 1995,23(12):1315-1324
[12]Mota LC, Barfield C, Hernandez JP, et al. Nonylphenol-mediated CYP induction is PXR-dependent: The use of humanized mice and human hepatocytes suggests that hPXR is less sensitive than mouse PXR to nonylphenol treatment. Toxicol Appl Pharmacol, 2011, 252(3):259-267
[13]Antolino-Lobo I, Meulenbelt J, Nijmeijer SM, et al. 3,4-methylenedioxymethamphetamine (MDMA) interacts with therapeutic drugs on CYP3A by inhibition of pregnane X receptor (PXR) activation and catalytic enzyme inhibition. Toxicol Lett, 2011,203(1):82-91
[14]Hasegawa M, Kapelyukh Y, Tahara H, et al. Quantitative Prediction of Human Pregnane X Receptor and Cytochrome P450 3A4 Mediated Drug-Drug Interaction in a Novel Multiple Humanized Mouse Line. Mol Pharmacol,2011,80(3):518-528
[15]Bolt HM. Rifampicin, a keystone inducer of drug metabolism: from Herbert Remmer's pioneering ideas to modern concepts. Drug Metab Rev, 2004, 36(3-4):497-509
[16]Lam JL, Shugarts SB, Okochi H, et al. Elucidating the effect of final-day dosing of rifampin in induction studies on hepatic drug disposition and metabolism. J Pharmacol Exp Ther, 2006, 319(2):864-870
[17]Lee JH, Cho YK, Jung YS, et al. Time-dependent effects of Klebsiella pneumoniae endotoxin on the telithromycin pharmacokinetics in rats; restoration of the parameters in 96-hour KPLPS rats to the control levels. Pulm Pharmacol Ther, 2008,21(6): 860-865
[18]Zhang X, Galinsky RE, Kimura RE, et al. Inhibition of CYP3A by erythromycin: in vitro-in vivo correlation in rats. Drug Metab Dispos, 2010, 38(1): 61-72
[19]ANTHONY J. DEMETRIS, KENNETH P. BATTS, AMAR P. DHILLON, et al. Banff Schema for Grading Liver Allograft Rejection: An International Consensus Document. Hepatology, 1997, 25(3):658-663
[20]Ormonde DG, de Boer WB, Kierath A, et al. Banff schema for grading liver allograft rejection: utility in clinical practice. Liver Transpl Surg, 1999, 5(4):261-268
[21]Ly VT, Brock B. Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. Chem Biol Interact,2011,193(2):109-118
[22]Ji HY, Liu KH, Lee H, et al. Corydaline Inhibits Multiple Cytochrome P450 and UDP-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes. Molecules, 2011,16(8):6591-6602
[23]Uesawa Y, Abe M, Fukuda E, et al. Construction of a model to estimate the CYP3A inhibitory effect of grapefruit juice. Pharmazie, 2011,66(7):525-528
[24]Zhao B, Waterman MR. Moonlighting cytochrome P450 monooxygenases. IUBMB Life, 2011,63(7):473-477
[25]Ramamoorthy A, Skaar TC. In silico identification of microRNAs predicted to regulate the drug metabolizing cytochrome P450 genes. Drug Metab Lett, 2011,5(2):126-131
[26]Flaman AS, Gravel C, Hashem AM, et al. The effect of interferon-α on the expression of cytochrome P450 3A4 in human hepatoma cells. Toxicol Appl Pharmacol, 2011,253(2): 130-136
[27]Modarai M, Suter A, Kortenkamp A, et al. The interaction potential of herbal medicinal products:a luminescence-based screening platform assessing effects on cytochrome P450 and its use with devil's claw (Harpagophyti radix) preparations. J Pharm Pharmacol, 2011, 63(3):429-438
[28]Thorn HA, Lundahl A, Schrickx JA, et al. Drug metabolism of CYP3A4, CYP2C9 and CYP2D6 substrates in pigs and humans. Eur J Pharm Sci, 2011,43(3):89-98
[29]El-Sayed WM. Effect of pregnane X receptor (PXR) prototype agonists on chemoprotective and drug metabolizing enzymes in mice. Eur J Pharmacol, 2011,660(2-3):291-297
[30]Kharasch ED, Francis A, London A, et al. Sensitivity of intravenous and oral alfentanil and pupillary miosis as minimal and noninvasive probes for hepatic and first-pass CYP3A induction. Clin Pharmacol Ther, 2011,90(1):100-108
[31]Smith EM, Wilson JY. Assessment of cytochrome P450 fluorometric substrates with rainbow trout and killifish exposed to dexamethasone, pregnenolone-16alpha-carbonitrile, rifampicin, and beta-naphthoflavone. Aquat Toxicol, 2010, 97(4): 324-333
[32]Shi D, Yang D, Yan B. Dexamethasone transcriptionally increases the expression of the pregnane X receptor and synergistically enhances pyrethroid esfenvalerate in the induction of cytochrome P450 3A23. Biochem Pharmacol, 2010, 80(8):1274-1283
[33]Ye X, Li W, Yan Y, et al. Effects of cytochrome P4503A inducer dexamethasone on the metabolism and toxicity of triptolide in rat. Toxicol Lett, 2010, 192(2): 212-220
[34]Johnson B, Adams L, Lu E, et al. Impact of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of ondansetron and dexamethasone. Support Care Cancer, 2009, 17(9): 1177-1785
[35]Sugiyama E, Kikuchi A, Inada M, et al. The use of (13) C-erythromycin as an in vivo probe to evaluate CYP3A-mediated drug interactions in rats. J Pharm Sci, 2011,100(9):3995-4005
[1]中华医学会器官移植学会肾移植组.他克莫司在临床肾移植中的应用指南.中华器官移植杂志,2010,31(9)：565-566
[2]唐孝达.器官移植后的个体化免疫抑制治疗.中华器官移植杂志,2010,31(3)：133-135
[3]Ware N, MacPhee IA. Current progress in pharmacogenetics and individualized immuno-suppressive drug dosing in organ transplantation. Curr Opin Mol Ther, 2010, 12(3): 270-283
[4]Baldini M, Bartolini E, Gori S, et al. Epilepsy after neuroimaging normalization in a woman with tacrolimus-related posterior reversible encephalopathy syndrome. Epilepsy Behav, 2010, 17(4):558-560
[5]Dehghani SM, Haghighat M, Imanieh MH, et al. Tacrolimus related hypertrophic cardiomyopathy in liver transplant recipients. Arch Iran Med, 2010, 13(2): 116-119
[6]Vearrier D, Simpson SE, Greenberg MI. Mutism and Persistent Dysarthria Due to Tacrolimus-Based Immunosuppression Following Allogeneic Liver Transplantation. Am J Ther, 2010 Jun 9. [Epub ahead of print]
[7]Yun J, Park KA, Oh SY. Bilateral ischemic optic neuropathy in a patient using tacrolimus (FK506) after liver transplantation. Transplantation, 2010, 89(12):1541-1542
[8]Yilmaz S, Gokben S, Arikan C, et al. Reversibility of cytotoxic edema in tacrolimus leukoencephalopathy. Pediatr Neurol, 2010, 43(5):359-362
[9]Burckart GJ, Amur S. Update on the clinical pharmacogenomics of organ transplantation. Pharmacogenomics, 2010, 11(2):227-236
[10]Mizuno S, Hamada T, Nakatani K, et al. Monitoring peripheral blood CD4+ adenosine triphosphate activity after living donor liver transplantation: impact of combination assays of immune function and CYP3A5 genotype. J Hepatobiliary Pancreat Sci, 2010, 18(2):226-232
[11]Zhang X, Wang Z, Fan J, et al. Impact of interleukin-10 gene polymorphisms on tacrolimus dosing requirements in Chinese liver transplant patients during the early posttransplantation period. Eur J Clin Pharmacol, 2011,67(8):803-813
[12]Oteo I, Lukas JC, Leal N, et al. Pathophysiological idiosyncrasies and pharmacokinetic realities may interfere with tacrolimus dose titration in liver transplantation. Eur J Clin Pharmacol,2011,67(7):671-679
[13]Ingelman-Sundberg M, Sim SC. Intronic polymorphisms of cytochromes P450. Hum Genomics,2010,4(6):402-405
[14]Thervet E, Loriot MA, Barbier S, et al. Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin Pharmacol Ther, 2010, 87(6):721-726
[15]Quteineh L, Verstuyft C. Pharmacogenetics in immunosuppressants:impact on dose requirement of calcineurin inhibitors in renal and liver pediatric transplant recipients. Curr Opin Organ Transplant, 2010, 15(5):601-607
[16]MacPhee IA, Holt DW. A pharmacogenetic strategy for immunosuppression based on the CYP3A5 genotype. Transplantation, 2008,85(2):163-165
[17]Barrera-Pulido L, Aguilera-Garcia I, Docobo-Perez F, et al. Clinical Relevance and Prevalence of Polymorphisms in CYP3A5 and MDR1 Genes That Encode Tacrolimus Biotransformation Enzymes in Liver Transplant Recipients. Transplant Proc, 2008, 40(9): 2949-2951
[18]Kreutz R, Bolbrinker J, van der Sman-de Beer F, et al. CYP3A5 genotype is associated with longer patient survival after kidney transplantation and long-term treatment with cyclosporine. Pharmacogenomics J, 2008,8(6):416-422
[19]Fukudo M, Yano I, Yoshimura A, et al. Impact of MDR1 and CYP3A5 on the oral clearance of tacrolimus and tacrolimus-related renal dysfunction in adult living-donor liver transplant patients. Pharmacogenet Genomics, 2008, 18(5):413-423
[20]Cavanaugh TM, Parrish N, Neff G, et al. The impact of a change in tacrolimus monitoring immunoassay techniques on clinical decision making. Prog Transplant, 2010, 20(4):350-356
[21]Joo DJ, Jung I, Kim MS, et al. Comparison of the affinity column-mediated immunoassay and microparticle enzyme immunoassay methods as a tacrolimus concentration assay in the early period after liver transplantation. Transplant Proc, 2010, 42(10):4137-4140
[22]Bazin C, Guinedor A, Barau C, et al. Evaluation of the Architect tacrolimus assay in kidney, liver, and heart transplant recipients. J Pharm Biomed Anal, 2010, 53(4):997-1002
[23]Park ES, Peccoud MR, Wicks KA, et al. Use of an automated clinical management system improves outpatient immunosuppressive care following liver transplantation. J Am Med Inform Assoc,2010,17(4):396-402
[24]Napoli KL, Hammett-Stabler C, Taylor PJ, et al. Multi-center evaluation of a commercial Kit for tacrolimus determination by LC/MS/MS. Clin Biochem, 2010, 43(10-11):910-920
[25]Marubashi S, Nagano H, Kobayashi S, et al. Evaluation of a new immunoassay for therapeutic drug monitoring of tacrolimus in adult liver transplant recipients. J Clin Pharmacol,2010,50(6):705-709
[26]Coto E, Tavira B. Pharmacogenetics of calcineurin inhibitors in renal transplantation. Transplantation, 2009, 88(3 Suppl):S62-67
[27]Larriba J, Imperiali N, Groppa R, et al. Pharmacogenetics of immunosuppressant polymorphism of CYP3A5 in renal transplant recipients. Transplant Proc, 2010, 42(1): 257-259
[28]Kuypers DR, Naesens M, de Jonge H, et al. Tacrolimus dose requirements and CYP3A5 genotype and the development of calcineurin inhibitor-associated nephrotoxicity in renal allograft recipients. Ther Drug Monit, 2010, 32(4):394-404
[29]Barry A, Levine M. A Systematic Review of the Effect of CYP3A5 Genotype on the Apparent Oral Clearance of Tacrolimus in Renal Transplant Recipients. Ther Drug Monit, 2010,32(6):708-714
[30]Capron A, Mourad M, De Meyer M, et al. CYP3A5 and ABCB1 polymorphisms influence tacrolimus concentrations in peripheral blood mononuclear cells after renal transplantation. Pharmacogenomics, 2010, 11(5):703-714
[31]van Gelder T, Hesselink DA. Dosing tacrolimus based on CYP3A5 genotype:will it improve clinical outcome? Clin Pharmacol Ther, 2010, 87(6):640-641
[32]Katsakiori PF, Papapetrou EP, Sakellaropoulos GC, et al. Factors affecting the long-term response to tacrolimus in renal transplant patients:pharmacokinetic and pharmacogenetic approach. Int J Med Sci, 2010, 7(2):94-100
[33]Tang HL, Ma LL, Xie HG, et al. Effects of the CYP3A5*3 variant on cyclosporine exposure and acute rejection rate in renal transplant patients:a meta-analysis. Pharmacogenet Genomics,2010,20(9):525-531
[34]Lukas JC, Calvo R, Zografidis A, et al. Simulation of sirolimus exposures and population variability immediately post renal transplantation: importance of the patient's CYP3A5 genotype in tailoring treatment. Biopharm Drug Dispos, 2010, 31(2-3):129-137
[35]Zhu HJ, Yuan SH, Fang Y, et al. The effect of CYP3A5 polymorphism on dose-adjusted cyclosporine concentration in renal transplant recipients:a meta-analysis. Pharmacogenomics J,2011,11(3):237-246
[36]Mateu LM, Jimenez Torres NV. Genetic polymorphisms and individualized tacrolimus dosing. Transplant Proc, 2010, 42(8):3031-3033
[37]Chen B, Zhang W, Fang J, et al. Influence of the MDR1 haplotype and CYP3A5 genotypes on cyclosporine blood level in Chinese renal transplant recipients. Xenobiotica, 2009, 39(12): 931-938
[38]Press RR, de Fijter JW, Guchelaar HJ. Individualizing calcineurin inhibitor therapy in renal transplantation-current limitations and perspectives. Curr Pharm Des, 2010, 16(2):176-186
[39]Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I. Clin Pharmacokinet,2010,49(3):141-175
[40]Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part Ⅱ. Clin Pharmacokinet, 2010, 49(4):207-221
[41]Grude P, Boleslawski E, Conti F, et al. MDR1 gene expression in peripheral blood mononuclear cells after liver transplantation. Transplantation, 2002, 73(11):1824-1828
[42]Ikemura K, Urano K, Matsuda H, et al. Decreased oral absorption of cyclosporine A after liver ischemia-reperfusion injury in rats: the contribution of CYP3A and P-glycoprotein to the first-pass metabolism in intestinal epithelial cells. J Pharmacol Exp Ther, 2009, 328(1): 249-255
[43]Yamauchi A, Dohgu S, Takata F, et al. Partial hepatectomy aggravates cyclosporin A-induced neurotoxicity by lowering the function of the blood-brain barrier in mice. Life Sci, 2011, 88(11-12):529-534
[44]Daoudaki M, Fouzas I, Stapf V, et al. Cyclosporine a augments P-glycoprotein expression in the regenerating rat liver. Biol Pharm Bull, 2003,26(3):303-307
[45]Fukudo M, Yano I, Masuda S, et al. Population pharmacokinetic and pharmacogenomic analysis of tacrolimus in pediatric living-donor liver transplant recipients. Clin Pharmacol Ther, 2006, 80(4):331-345
[46]Masuda S, Goto M, Fukatsu S, et al. Intestinal MDR1/ABCB1 level at surgery as a risk factor of acute cellular rejection in living-donor liver transplant patients. Clin Pharmacol Ther, 2006, 79(1):90-102
[47]Masuda S, Goto M, Okuda M, et al. Initial dosage adjustment for oral administration of tacrolimus using the intestinal MDR1 level in living-donor liver transplant recipients. Transplant Proc,2005,37(4): 1728-1729
[48]Goto M, Masuda S, Kiuchi T, et al. Relation between mRNA expression level of multidrug resistance 1/ABCB 1 in blood cells and required level of tacrolimus in pediatric living-donor liver transplantation. J Pharmacol Exp Ther, 2008, 325(2):610-616
[49]Hosohata K, Masuda S, Yonezawa A, et al. MDRl haplotypes conferring an increased expression of intestinal CYP3A4 rather than MDR1 in female living-donor liver transplant patients. Pharm Res, 2009, 26(7):1590-1595
[50]Hawwa AF, McKiernan PJ, Shields M, et al. Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant. Br J Clin Pharmacol, 2009, 68(3): 413-421
[51]Bonhomme-Faivre L, Picard V, Saliba F, et al. Effect of the ABCB1 3435C?T polymorphism on tacrolimus concentrations and dosage requirements in liver transplant recipients. Am J Health Syst Pharm, 2009, 66(18):1645-1651
[2]Marudanayagam R, Shanmugam V, Sandhu B, et al. Liver retransplantation in adults:a single-centre, 25-year experience. HPB (Oxford), 2010, 12(3): 217-224
[3]Tan HH, Martin P. Management of end-stage liver disease in chronic hepatitis B. Clin Liver Dis,2010,14(3):477-493
[4]Movahedi Z, Holt CD, Saab S. Liver transplant: a primer. Exp Clin Transplant, 2010, 8(2): 83-90
[5]Miyazaki ET, Dos Santos R Jr, Miyazaki MC, et al. Patients on the waiting list for liver transplantation: caregiver burden and stress. Liver Transpl, 2010, 16(10):1164-1168
[6]Kuriyama N, Isaji S, Hamada T, et al. Activated protein C prevents hepatic ischaemia-reperfusion injury in rats. Liver Int, 2009, 29(2):299-307
[7]Junnarkar SP, Tapuria N, Dutt N, et al. Bucillamine improves hepatic microcirculation and reduces hepatocellular injury after liver warm ischaemia-reperfusion injury. HPB (Oxford), 2009,11(3):264-273
[8]Hilmi IA, Peng Z, Planinsic RM, et al. N-acetylcysteine does not prevent hepatorenal ischaemia-reperfusion injury in patients undergoing orthotopic liver transplantation. Nephrol Dial Transplant, 2010, 25(7):2328-2333
[9]Andreani P, Hoti E, de la Serna S, et al. Ischaemic preconditioning of the graft in adult living related right lobe liver transplantation: impact on ischaemia-reperfusion injury and clinical relevance. HPB (Oxford), 2010, 12(7):439-446
[10]Jegatheeswaran S, Siriwardena AK. Experimental and clinical evidence for modification of hepatic ischaemia-reperfusion injury by N-acetylcysteine during major liver surgery. HPB (Oxford),2011,13(3):71-78
[11]Martins PN, Chang S, Mahadevapa B, et al. Liver grafts from selected older donors do not have significantly more ischaemia reperfusion injury. HPB (Oxford), 2011,13(3):212-220
[12]Suzuki S, Toledo-Pereyra LH, Rodriguez FJ, et al. Neutrophil infiltration as an important factor in liver ischemia and reperfusion injury. Modulating effects of FK506 and cyclosporine. Transplantation, 1993,55(6):1265-1272.
[13]Lee S, Charters AC, Chandler JG, et al. A technique for orthotopic liver transplantation in the rat. Transplantation, 1973,16(6):664-669
[14]Kamada N, Calne RY. A surgical experience with five hundred thirty liver transplants in the rat. Surgery, 1983,93(1 pt 1):64-69
[15]Miyata M, Fischer JH, Fuhs M, et al. A simple method for orthotopic liver transplantation in the rat. Cuff technique for three vascular anastomoses. Transplantation, 1980, 30(5): 335-338
[16]刘静,陈福,陈达丰等.改良双袖套法大鼠原位肝移植500例.世界华人消化杂志,2008,16(22)：2521-2524
[17]Matevossian E, Doll D, Huser N, et al. Liver transplantation in the rat: single-center experience with technique, long-ienn survival, and functional and histolugic findings. Transplant Proc, 2009, 41(6): 2631-2636
[18]Hang HL, Qiu YD, Zhu XH, et al. A novel model for external biliary drainage in rat orthotopic liver transplantation. Int J Artif Organs, 2008, 31(12): 1055-1058
[19]Glanemann M, Gaebelein G, Nussler N, et al. Transplantation of monocyte-derived hepatocyte-like cells (NeoHeps) improves survival in a model of acute liver failure. Ann Surg, 2009,249(1):149-154
[20]Ariyakhagom V, Schmitz V, Olschewski P, et al. Improvement of microsurgical techniques in orthotopic rat liver transplantation. J Surg Res, 2009, 153(2): 332-339
[21]Oldani G, Maestri M, Gaspari A, et al. A novel technique for rat liver transplantation using Quick Linker system: a preliminary result. J Surg Res, 2008, 149(2):303-309
[22]Seppen J, Filali EE, Elferink RO. Small animal models of hepatocyte transplantation. Methods Mol Biol,2009,481(8):75-82
[23]刘其雨,程若川,苏艳军等.双套管法制作大鼠胰十二指肠移植模型.中国普外基础与临床杂志,2007,14(4)：420-422
[24]Carpenter AJ, Follette DM, Sheppard B, et al. Simultaneous antegrade and retrograde reperfusion after cardioplegic arrest for coronary artery bypass. J Card Surg, 1999, 14(5): 354-358
[25]Kertsman VP, Kambarov SU, Mishra YK, et al. Antegrade and retrograde cardioplegia with different reperfusion techniques in patients with multiple coronary artery lesions. Indian Heart J,1992,44(2):103-107
[26]Matevossian E, Doll D, Huser N, et al. Liver transplantation in the rat: single-center experience with technique, long-term survival, and functional and histologic findings. Transplant Proc, 2009, 41(6): 2631-2636
[27]Heidenhain C, Heise M, Jonas S, et al. Retrograde reperfusion via vena cava lowers the risk of initial nonfunction but increases the risk of ischemic-type biliary lesions in liver transplantation-a randomized clinical trial. Transpl Int, 2006, 19(9):738-748
[28]Daniela K, Michael Z, Florian I, et al. Influence of retrograde flushing via the caval vein on the post-reperfusion syndrome in liver transplantation. Clin Transplant, 2004, 18(6):638-641
[29]Chen J, Singhapricha T, Hu KQ, et al. Postliver transplant acute renal injury and failure by the RIFLE criteria in patients with normal pretransplant serum creatinine concentrations:a matched study. Transplantation, 2011,91(3):348-353
[30]Kern H, Bald C, Brill T, et al. The influence of retrograde reperfusion on the ischaemia-/reperfusion injury after liver transplantation in the rat. Int J Exp Pathol, 2008, 89(6):433-437
[1]Castroagudin JF, Molina E, Varo E. Calcineurin inhibitors in liver transplantation: to be or not to be. Transplant Proc, 2011,43(6): 2220-2223
[2]Kelly D. Safety and efficacy of tacrolimus in pediatric liver recipients. Pediatr Transplant, 2011,15(1):19-24
[3]O'Leary JG, Trotter JF, Neri MA, et al. Effect of tacrolimus on survival in hepatitis C-infected patients after liver transplantation. Proc (Bayl Univ Med Cent), 2011,24(3):187-191
[4]Perez MJ, Garcia DM, Taybi BJ, et al. Cardiovascular risk factors after liver transplantation: analysis of related factors. Transplant Proc, 2011,43(3):739-741
[5]Masood MQ, Rabbani M, Jafri W, et al. Diabetic ketoacidosis associated with tacrolimus in solid organ transplant recipients. J Pak Med Assoc, 2011,61(3):288-290
[6]Koh T, Baek SH, Han JI, et al. Maculopathy associated with tacrolimus (FK 506). Korean J Ophthalmol, 2011,25(1):69-71
[7]Zhang HL. Tacrolimus leukoencephalopathy-is it posterior reversible encephalopathy syndrome? Pediatr Neurol, 2011,44(3):236
[8]Garces G, Contreras G, Carvalho D, et al. Chronic kidney disease after orthotopic liver transplantation in recipients receiving tacrolimus. Clin Nephrol, 2011,75(2): 150-157
[9]Metalidis C, Lerut E, Naesens M, et al. Expression of CYP3A5 and P-glycoprotein in renal allografts with histological signs of calcineurin inhibitor nephrotoxicity. Transplantation, 2011,91(10):1098-1102
[10]Herrero MJ, Sanchez-Plumed J, Galiana M, et al. Influence of pharmacogenetic polymorphisms in routine immunosuppression therapy after renal transplantation. Transplant Proc,2010,42(8):3134-3136
[11]Lampen A, Christians U, Guengerich FP, et al. Metabolism of the immunosuppressant tacrolimus in the small intestine: cytochrome P450, drug interactions, and interindividual variability. Drug Metab Dispos, 1995,23(12):1315-1324
[12]Mota LC, Barfield C, Hernandez JP, et al. Nonylphenol-mediated CYP induction is PXR-dependent: The use of humanized mice and human hepatocytes suggests that hPXR is less sensitive than mouse PXR to nonylphenol treatment. Toxicol Appl Pharmacol, 2011, 252(3):259-267
[13]Antolino-Lobo I, Meulenbelt J, Nijmeijer SM, et al. 3,4-methylenedioxymethamphetamine (MDMA) interacts with therapeutic drugs on CYP3A by inhibition of pregnane X receptor (PXR) activation and catalytic enzyme inhibition. Toxicol Lett, 2011,203(1):82-91
[14]Hasegawa M, Kapelyukh Y, Tahara H, et al. Quantitative Prediction of Human Pregnane X Receptor and Cytochrome P450 3A4 Mediated Drug-Drug Interaction in a Novel Multiple Humanized Mouse Line. Mol Pharmacol,2011,80(3):518-528
[15]Bolt HM. Rifampicin, a keystone inducer of drug metabolism: from Herbert Remmer's pioneering ideas to modern concepts. Drug Metab Rev, 2004, 36(3-4):497-509
[16]Lam JL, Shugarts SB, Okochi H, et al. Elucidating the effect of final-day dosing of rifampin in induction studies on hepatic drug disposition and metabolism. J Pharmacol Exp Ther, 2006, 319(2):864-870
[17]Lee JH, Cho YK, Jung YS, et al. Time-dependent effects of Klebsiella pneumoniae endotoxin on the telithromycin pharmacokinetics in rats; restoration of the parameters in 96-hour KPLPS rats to the control levels. Pulm Pharmacol Ther, 2008,21(6): 860-865
[18]Zhang X, Galinsky RE, Kimura RE, et al. Inhibition of CYP3A by erythromycin: in vitro-in vivo correlation in rats. Drug Metab Dispos, 2010, 38(1): 61-72
[19]ANTHONY J. DEMETRIS, KENNETH P. BATTS, AMAR P. DHILLON, et al. Banff Schema for Grading Liver Allograft Rejection: An International Consensus Document. Hepatology, 1997, 25(3):658-663
[20]Ormonde DG, de Boer WB, Kierath A, et al. Banff schema for grading liver allograft rejection: utility in clinical practice. Liver Transpl Surg, 1999, 5(4):261-268
[21]Ly VT, Brock B. Effects of CYP inhibitors on precocene I metabolism and toxicity in rat liver slices. Chem Biol Interact,2011,193(2):109-118
[22]Ji HY, Liu KH, Lee H, et al. Corydaline Inhibits Multiple Cytochrome P450 and UDP-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes. Molecules, 2011,16(8):6591-6602
[23]Uesawa Y, Abe M, Fukuda E, et al. Construction of a model to estimate the CYP3A inhibitory effect of grapefruit juice. Pharmazie, 2011,66(7):525-528
[24]Zhao B, Waterman MR. Moonlighting cytochrome P450 monooxygenases. IUBMB Life, 2011,63(7):473-477
[25]Ramamoorthy A, Skaar TC. In silico identification of microRNAs predicted to regulate the drug metabolizing cytochrome P450 genes. Drug Metab Lett, 2011,5(2):126-131
[26]Flaman AS, Gravel C, Hashem AM, et al. The effect of interferon-α on the expression of cytochrome P450 3A4 in human hepatoma cells. Toxicol Appl Pharmacol, 2011,253(2): 130-136
[27]Modarai M, Suter A, Kortenkamp A, et al. The interaction potential of herbal medicinal products:a luminescence-based screening platform assessing effects on cytochrome P450 and its use with devil's claw (Harpagophyti radix) preparations. J Pharm Pharmacol, 2011, 63(3):429-438
[28]Thorn HA, Lundahl A, Schrickx JA, et al. Drug metabolism of CYP3A4, CYP2C9 and CYP2D6 substrates in pigs and humans. Eur J Pharm Sci, 2011,43(3):89-98
[29]El-Sayed WM. Effect of pregnane X receptor (PXR) prototype agonists on chemoprotective and drug metabolizing enzymes in mice. Eur J Pharmacol, 2011,660(2-3):291-297
[30]Kharasch ED, Francis A, London A, et al. Sensitivity of intravenous and oral alfentanil and pupillary miosis as minimal and noninvasive probes for hepatic and first-pass CYP3A induction. Clin Pharmacol Ther, 2011,90(1):100-108
[31]Smith EM, Wilson JY. Assessment of cytochrome P450 fluorometric substrates with rainbow trout and killifish exposed to dexamethasone, pregnenolone-16alpha-carbonitrile, rifampicin, and beta-naphthoflavone. Aquat Toxicol, 2010, 97(4): 324-333
[32]Shi D, Yang D, Yan B. Dexamethasone transcriptionally increases the expression of the pregnane X receptor and synergistically enhances pyrethroid esfenvalerate in the induction of cytochrome P450 3A23. Biochem Pharmacol, 2010, 80(8):1274-1283
[33]Ye X, Li W, Yan Y, et al. Effects of cytochrome P4503A inducer dexamethasone on the metabolism and toxicity of triptolide in rat. Toxicol Lett, 2010, 192(2): 212-220
[34]Johnson B, Adams L, Lu E, et al. Impact of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of ondansetron and dexamethasone. Support Care Cancer, 2009, 17(9): 1177-1785
[35]Sugiyama E, Kikuchi A, Inada M, et al. The use of (13) C-erythromycin as an in vivo probe to evaluate CYP3A-mediated drug interactions in rats. J Pharm Sci, 2011,100(9):3995-4005
[1]中华医学会器官移植学会肾移植组.他克莫司在临床肾移植中的应用指南.中华器官移植杂志,2010,31(9)：565-566
[2]唐孝达.器官移植后的个体化免疫抑制治疗.中华器官移植杂志,2010,31(3)：133-135
[3]Ware N, MacPhee IA. Current progress in pharmacogenetics and individualized immuno-suppressive drug dosing in organ transplantation. Curr Opin Mol Ther, 2010, 12(3): 270-283
[4]Baldini M, Bartolini E, Gori S, et al. Epilepsy after neuroimaging normalization in a woman with tacrolimus-related posterior reversible encephalopathy syndrome. Epilepsy Behav, 2010, 17(4):558-560
[5]Dehghani SM, Haghighat M, Imanieh MH, et al. Tacrolimus related hypertrophic cardiomyopathy in liver transplant recipients. Arch Iran Med, 2010, 13(2): 116-119
[6]Vearrier D, Simpson SE, Greenberg MI. Mutism and Persistent Dysarthria Due to Tacrolimus-Based Immunosuppression Following Allogeneic Liver Transplantation. Am J Ther, 2010 Jun 9. [Epub ahead of print]
[7]Yun J, Park KA, Oh SY. Bilateral ischemic optic neuropathy in a patient using tacrolimus (FK506) after liver transplantation. Transplantation, 2010, 89(12):1541-1542
[8]Yilmaz S, Gokben S, Arikan C, et al. Reversibility of cytotoxic edema in tacrolimus leukoencephalopathy. Pediatr Neurol, 2010, 43(5):359-362
[9]Burckart GJ, Amur S. Update on the clinical pharmacogenomics of organ transplantation. Pharmacogenomics, 2010, 11(2):227-236
[10]Mizuno S, Hamada T, Nakatani K, et al. Monitoring peripheral blood CD4+ adenosine triphosphate activity after living donor liver transplantation: impact of combination assays of immune function and CYP3A5 genotype. J Hepatobiliary Pancreat Sci, 2010, 18(2):226-232
[11]Zhang X, Wang Z, Fan J, et al. Impact of interleukin-10 gene polymorphisms on tacrolimus dosing requirements in Chinese liver transplant patients during the early posttransplantation period. Eur J Clin Pharmacol, 2011,67(8):803-813
[12]Oteo I, Lukas JC, Leal N, et al. Pathophysiological idiosyncrasies and pharmacokinetic realities may interfere with tacrolimus dose titration in liver transplantation. Eur J Clin Pharmacol,2011,67(7):671-679
[13]Ingelman-Sundberg M, Sim SC. Intronic polymorphisms of cytochromes P450. Hum Genomics,2010,4(6):402-405
[14]Thervet E, Loriot MA, Barbier S, et al. Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin Pharmacol Ther, 2010, 87(6):721-726
[15]Quteineh L, Verstuyft C. Pharmacogenetics in immunosuppressants:impact on dose requirement of calcineurin inhibitors in renal and liver pediatric transplant recipients. Curr Opin Organ Transplant, 2010, 15(5):601-607
[16]MacPhee IA, Holt DW. A pharmacogenetic strategy for immunosuppression based on the CYP3A5 genotype. Transplantation, 2008,85(2):163-165
[17]Barrera-Pulido L, Aguilera-Garcia I, Docobo-Perez F, et al. Clinical Relevance and Prevalence of Polymorphisms in CYP3A5 and MDR1 Genes That Encode Tacrolimus Biotransformation Enzymes in Liver Transplant Recipients. Transplant Proc, 2008, 40(9): 2949-2951
[18]Kreutz R, Bolbrinker J, van der Sman-de Beer F, et al. CYP3A5 genotype is associated with longer patient survival after kidney transplantation and long-term treatment with cyclosporine. Pharmacogenomics J, 2008,8(6):416-422
[19]Fukudo M, Yano I, Yoshimura A, et al. Impact of MDR1 and CYP3A5 on the oral clearance of tacrolimus and tacrolimus-related renal dysfunction in adult living-donor liver transplant patients. Pharmacogenet Genomics, 2008, 18(5):413-423
[20]Cavanaugh TM, Parrish N, Neff G, et al. The impact of a change in tacrolimus monitoring immunoassay techniques on clinical decision making. Prog Transplant, 2010, 20(4):350-356
[21]Joo DJ, Jung I, Kim MS, et al. Comparison of the affinity column-mediated immunoassay and microparticle enzyme immunoassay methods as a tacrolimus concentration assay in the early period after liver transplantation. Transplant Proc, 2010, 42(10):4137-4140
[22]Bazin C, Guinedor A, Barau C, et al. Evaluation of the Architect tacrolimus assay in kidney, liver, and heart transplant recipients. J Pharm Biomed Anal, 2010, 53(4):997-1002
[23]Park ES, Peccoud MR, Wicks KA, et al. Use of an automated clinical management system improves outpatient immunosuppressive care following liver transplantation. J Am Med Inform Assoc,2010,17(4):396-402
[24]Napoli KL, Hammett-Stabler C, Taylor PJ, et al. Multi-center evaluation of a commercial Kit for tacrolimus determination by LC/MS/MS. Clin Biochem, 2010, 43(10-11):910-920
[25]Marubashi S, Nagano H, Kobayashi S, et al. Evaluation of a new immunoassay for therapeutic drug monitoring of tacrolimus in adult liver transplant recipients. J Clin Pharmacol,2010,50(6):705-709
[26]Coto E, Tavira B. Pharmacogenetics of calcineurin inhibitors in renal transplantation. Transplantation, 2009, 88(3 Suppl):S62-67
[27]Larriba J, Imperiali N, Groppa R, et al. Pharmacogenetics of immunosuppressant polymorphism of CYP3A5 in renal transplant recipients. Transplant Proc, 2010, 42(1): 257-259
[28]Kuypers DR, Naesens M, de Jonge H, et al. Tacrolimus dose requirements and CYP3A5 genotype and the development of calcineurin inhibitor-associated nephrotoxicity in renal allograft recipients. Ther Drug Monit, 2010, 32(4):394-404
[29]Barry A, Levine M. A Systematic Review of the Effect of CYP3A5 Genotype on the Apparent Oral Clearance of Tacrolimus in Renal Transplant Recipients. Ther Drug Monit, 2010,32(6):708-714
[30]Capron A, Mourad M, De Meyer M, et al. CYP3A5 and ABCB1 polymorphisms influence tacrolimus concentrations in peripheral blood mononuclear cells after renal transplantation. Pharmacogenomics, 2010, 11(5):703-714
[31]van Gelder T, Hesselink DA. Dosing tacrolimus based on CYP3A5 genotype:will it improve clinical outcome? Clin Pharmacol Ther, 2010, 87(6):640-641
[32]Katsakiori PF, Papapetrou EP, Sakellaropoulos GC, et al. Factors affecting the long-term response to tacrolimus in renal transplant patients:pharmacokinetic and pharmacogenetic approach. Int J Med Sci, 2010, 7(2):94-100
[33]Tang HL, Ma LL, Xie HG, et al. Effects of the CYP3A5*3 variant on cyclosporine exposure and acute rejection rate in renal transplant patients:a meta-analysis. Pharmacogenet Genomics,2010,20(9):525-531
[34]Lukas JC, Calvo R, Zografidis A, et al. Simulation of sirolimus exposures and population variability immediately post renal transplantation: importance of the patient's CYP3A5 genotype in tailoring treatment. Biopharm Drug Dispos, 2010, 31(2-3):129-137
[35]Zhu HJ, Yuan SH, Fang Y, et al. The effect of CYP3A5 polymorphism on dose-adjusted cyclosporine concentration in renal transplant recipients:a meta-analysis. Pharmacogenomics J,2011,11(3):237-246
[36]Mateu LM, Jimenez Torres NV. Genetic polymorphisms and individualized tacrolimus dosing. Transplant Proc, 2010, 42(8):3031-3033
[37]Chen B, Zhang W, Fang J, et al. Influence of the MDR1 haplotype and CYP3A5 genotypes on cyclosporine blood level in Chinese renal transplant recipients. Xenobiotica, 2009, 39(12): 931-938
[38]Press RR, de Fijter JW, Guchelaar HJ. Individualizing calcineurin inhibitor therapy in renal transplantation-current limitations and perspectives. Curr Pharm Des, 2010, 16(2):176-186
[39]Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I. Clin Pharmacokinet,2010,49(3):141-175
[40]Staatz CE, Goodman LK, Tett SE. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part Ⅱ. Clin Pharmacokinet, 2010, 49(4):207-221
[41]Grude P, Boleslawski E, Conti F, et al. MDR1 gene expression in peripheral blood mononuclear cells after liver transplantation. Transplantation, 2002, 73(11):1824-1828
[42]Ikemura K, Urano K, Matsuda H, et al. Decreased oral absorption of cyclosporine A after liver ischemia-reperfusion injury in rats: the contribution of CYP3A and P-glycoprotein to the first-pass metabolism in intestinal epithelial cells. J Pharmacol Exp Ther, 2009, 328(1): 249-255
[43]Yamauchi A, Dohgu S, Takata F, et al. Partial hepatectomy aggravates cyclosporin A-induced neurotoxicity by lowering the function of the blood-brain barrier in mice. Life Sci, 2011, 88(11-12):529-534
[44]Daoudaki M, Fouzas I, Stapf V, et al. Cyclosporine a augments P-glycoprotein expression in the regenerating rat liver. Biol Pharm Bull, 2003,26(3):303-307
[45]Fukudo M, Yano I, Masuda S, et al. Population pharmacokinetic and pharmacogenomic analysis of tacrolimus in pediatric living-donor liver transplant recipients. Clin Pharmacol Ther, 2006, 80(4):331-345
[46]Masuda S, Goto M, Fukatsu S, et al. Intestinal MDR1/ABCB1 level at surgery as a risk factor of acute cellular rejection in living-donor liver transplant patients. Clin Pharmacol Ther, 2006, 79(1):90-102
[47]Masuda S, Goto M, Okuda M, et al. Initial dosage adjustment for oral administration of tacrolimus using the intestinal MDR1 level in living-donor liver transplant recipients. Transplant Proc,2005,37(4): 1728-1729
[48]Goto M, Masuda S, Kiuchi T, et al. Relation between mRNA expression level of multidrug resistance 1/ABCB 1 in blood cells and required level of tacrolimus in pediatric living-donor liver transplantation. J Pharmacol Exp Ther, 2008, 325(2):610-616
[49]Hosohata K, Masuda S, Yonezawa A, et al. MDRl haplotypes conferring an increased expression of intestinal CYP3A4 rather than MDR1 in female living-donor liver transplant patients. Pharm Res, 2009, 26(7):1590-1595
[50]Hawwa AF, McKiernan PJ, Shields M, et al. Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant. Br J Clin Pharmacol, 2009, 68(3): 413-421
[51]Bonhomme-Faivre L, Picard V, Saliba F, et al. Effect of the ABCB1 3435C?T polymorphism on tacrolimus concentrations and dosage requirements in liver transplant recipients. Am J Health Syst Pharm, 2009, 66(18):1645-1651