雷替曲塞经不同给药方式的药动学分析
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摘要
目的通过兔肝VX2肿瘤模型,考察雷替曲塞经股静脉灌注、肝动脉灌注、肝动脉碘油混悬液注入、肝动脉灌注后明胶海绵栓塞给药的药动学情况。方法将40只VX2肝肿瘤模型新西兰兔按雷替曲塞不同给药方式随机分成股静脉灌注(A)组、肝动脉灌注(B)组、肝动脉碘油混悬液灌注(C)组、肝动脉灌注后明胶海绵栓塞(D)组,用LC-MS/MS法测定血浆中雷替曲塞的浓度,并计算药动学参数。结果 A,B,C,D 4组给药后,t_(max)均为5 min;t_(1/2)分别为(5.88±1.39),(7.31±2.60),(9.86±5.10),(7.19±2.27),其中C组t_(1/2)最长,与A组相比差异有统计学意义(P<0.05);C_(max)分别为(2 056.40±139.17),(1 389.21±180.28),(911.84±105.62),(1 133.41±181.42)ng·ml~(-1)·h~(-1),A组C_(max)明显高于B,C,D 3组,差异有统计学差异(P<0.05),其中C组最低;AUC_(0-t)分别为(5 482.72±1 007.07),(4 156.99±1 475.77),(2 785.13±1107.36),(3 903.64±947.25)ng·ml~(-1)·h~(-1)。A组AUC_(0-t)明显高于B,C,D 3组,差异有统计学意义(P<0.05),其中C组最低。结论与经股静脉灌注相比,雷替曲塞经肝动脉灌注、肝动脉碘油混悬液注入、肝动脉灌注后明胶海绵栓塞有可能使药物更多沉积在肿瘤区,增加局部药物浓度,可能增强其疗效,同时降低血浆中药物浓度,减轻副作用。
ObjectiveTo study the pharmacokinetics of raltitrexed using different ways of drug delivery,including femoral venous infusion,hepatic artery perfusion,hepatic artery injection of lipiodol suspension,hepatic artery perfusion followed by embolization with Gelfoam.MethodsAccording to the administration way of raltitrexed,a total of 40 New Zealand rabbit models with VX2 liver tumor were randomly divided into group A(femoral venous perfusion),group B(hepatic arterial perfusion),group C(hepatic artery injection of lipiodol suspension),and group D(hepatic artery perfusion followed by embolization with Gelfoam).Drug concentration in plasma were determined by using LC-MS/MS method and the pharmacokinetic parameters were calculated.ResultsAfter administration of raltitrexed,the Tmax was 5minutes in all 4 groups.In group A,B,C and D,the t_(1/2)(h)values were(5.88±1.39),(7.31±2.60),(9.86±5.10)and(7.19±2.27)respectively,with group C having the longest t_(1/2)value,which was significantly different with that of group A(P<0.05);the C_(max)(ng·ml~(-1)·h~(-1))values were(2 056.40±139.17),(1 389.21±180.28),(911.84±105.62)and(1 133.41±181.42)respectively,with the value of group A being obviously higher than that of group B,C and D(P<0.05)and the value of group C being the lowest;the AUC_(0-t)(ng·ml~(-1)·h~(-1))values were(5 482.72±1 007.07),(4 156.99±1 475.77),(2 785.13±1 107.36)and(3 903.64±947.25)respectively,with the value of group A being remarkably higher than that of group B,C and D(P<0.05)and the value of group C being the lowest.Conclusion Compared with the femoral vein infusion way,the ways of hepatic artery infusion,hepatic artery lipiodol suspension injection and hepatic artery perfusion followed by embolization with Gelfoam may promote more raltitrexed to deposit in the tumor area,thus,the curative effect is enhanced,the drug concentration in plasma is lowered and the side effects are alleviated.
ObjectiveTo study the pharmacokinetics of raltitrexed using different ways of drug delivery,including femoral venous infusion,hepatic artery perfusion,hepatic artery injection of lipiodol suspension,hepatic artery perfusion followed by embolization with Gelfoam.MethodsAccording to the administration way of raltitrexed,a total of 40 New Zealand rabbit models with VX2 liver tumor were randomly divided into group A(femoral venous perfusion),group B(hepatic arterial perfusion),group C(hepatic artery injection of lipiodol suspension),and group D(hepatic artery perfusion followed by embolization with Gelfoam).Drug concentration in plasma were determined by using LC-MS/MS method and the pharmacokinetic parameters were calculated.ResultsAfter administration of raltitrexed,the Tmax was 5minutes in all 4 groups.In group A,B,C and D,the t_(1/2)(h)values were(5.88±1.39),(7.31±2.60),(9.86±5.10)and(7.19±2.27)respectively,with group C having the longest t_(1/2)value,which was significantly different with that of group A(P<0.05);the C_(max)(ng·ml~(-1)·h~(-1))values were(2 056.40±139.17),(1 389.21±180.28),(911.84±105.62)and(1 133.41±181.42)respectively,with the value of group A being obviously higher than that of group B,C and D(P<0.05)and the value of group C being the lowest;the AUC_(0-t)(ng·ml~(-1)·h~(-1))values were(5 482.72±1 007.07),(4 156.99±1 475.77),(2 785.13±1 107.36)and(3 903.64±947.25)respectively,with the value of group A being remarkably higher than that of group B,C and D(P<0.05)and the value of group C being the lowest.Conclusion Compared with the femoral vein infusion way,the ways of hepatic artery infusion,hepatic artery lipiodol suspension injection and hepatic artery perfusion followed by embolization with Gelfoam may promote more raltitrexed to deposit in the tumor area,thus,the curative effect is enhanced,the drug concentration in plasma is lowered and the side effects are alleviated.
引文
[1]Barni S,G hidini A,Coinu A,et al.A systematic review of raltitrexed-based first-line chemotherapy in advanced colorectal cancer[J].Anticancer Drugs,2014,25:1122-1128.
[2]张鑫,朱林忠,朱旭,等.雷替曲塞持续动脉灌注化疗的药动学研究[J].中国实验诊断学,2016,20:8-11.
[3]陈平.雷替曲塞在大鼠血浆和脑组织中的分布研究[J].安徽医学,2013,34:174-176.
[4]Qi X,Wang D,Su C,et al.Hepatic resection versus transarterial chemoembolization for the initial treatment of hepatocellular carcinoma:a systematic review and meta-analysis[J].Oncotarget,2015,6:18715-18733.
[5]Qi X,Liu L,Wang D,et al.Hepatic resection alone versus in combination with pre-and post-operative transarterial chemoembolization for the treatment of hepatocellular carcinoma:A systematic review and meta-analysis[J].Oncotarget,2015,6:36838-36859.
[6]许飞,李忱瑞,孙伟,等.原发性肝癌TACE术中雷替曲塞的临床应用[J].介入放射学杂志,2017,26:418-421.
[7]Kim DW,Talati C,Kim R.Hepatocellular carcinoma(HCC):beyond sorafenib-chemotherapy[J].J Gastrointest Oncol,2017,8:256-265.
[8]Arai Y,Takeuchi Y,Inaba Y,et al.Percutaneous catheter placement for hepatic arterial infusion chemotherapy[J].Tech Vasc Interv Radiol,2007,10:30-37.
[9]Maurer CA,Borner M,Buchler MW,et al.Regional chemotherapy of gastrointestinal cancer[J].Dig Surg,1997,14:9-22.
[10]Beale P,Judson I,Hanwell J.Metabolism,excretion and pharmacokinetics of a single dose of 14C-raltitrexed in cancer patients[J].Cancer Chemother Pharmacol,1998,42:71-76.
[11]孙宾,李兴,宋杰,等.进展期胃癌术前介入治疗的临床应用[J].实用放射学杂志,2014,27:2054-2057.
[12]王良忠,李宁毅,马霖,等.氟尿嘧啶和卡铂周围静脉给药与舌动脉灌注栓塞后药动学实验研究[J].齐鲁医学杂志,2006,21:193-196.
[13]Stefanini GF,Anorati P,Biselli M,et al.Efficacy of transarterial targeted treatments on survival of patients with hepatpcellular carcinoma.An Italian experience[J].Cancer,1995,75:2427-2434.
[14]贺红杰,宋磊,赵丹懿,等.雷替曲塞联合奥沙利铂经TACE治疗不可切除肝癌患者的疗效评价[J].介入放射学杂志,2016,25:40-43.
[15]Kameyama M,Imaoka S,Fukuda I,et al.Delayed washout of intratumor blood flow is associated with good response to intraarteral chemoembolization for liver metastasis of colorectal cancer[J].Surgery,1993,114:97-101.
[16]Shigehara K,Kitagawa Y,Nakashima T,et al.Squamous cell carcinoma of the bladder:a patient treated successfully with a new combined chemotherapy regimen,intraarterial nedaplatin and pirarubicin plus intravenous methotrexate and vincristine[J].Int J CIin oncol,2006,1l:329-331.
[2]张鑫,朱林忠,朱旭,等.雷替曲塞持续动脉灌注化疗的药动学研究[J].中国实验诊断学,2016,20:8-11.
[3]陈平.雷替曲塞在大鼠血浆和脑组织中的分布研究[J].安徽医学,2013,34:174-176.
[4]Qi X,Wang D,Su C,et al.Hepatic resection versus transarterial chemoembolization for the initial treatment of hepatocellular carcinoma:a systematic review and meta-analysis[J].Oncotarget,2015,6:18715-18733.
[5]Qi X,Liu L,Wang D,et al.Hepatic resection alone versus in combination with pre-and post-operative transarterial chemoembolization for the treatment of hepatocellular carcinoma:A systematic review and meta-analysis[J].Oncotarget,2015,6:36838-36859.
[6]许飞,李忱瑞,孙伟,等.原发性肝癌TACE术中雷替曲塞的临床应用[J].介入放射学杂志,2017,26:418-421.
[7]Kim DW,Talati C,Kim R.Hepatocellular carcinoma(HCC):beyond sorafenib-chemotherapy[J].J Gastrointest Oncol,2017,8:256-265.
[8]Arai Y,Takeuchi Y,Inaba Y,et al.Percutaneous catheter placement for hepatic arterial infusion chemotherapy[J].Tech Vasc Interv Radiol,2007,10:30-37.
[9]Maurer CA,Borner M,Buchler MW,et al.Regional chemotherapy of gastrointestinal cancer[J].Dig Surg,1997,14:9-22.
[10]Beale P,Judson I,Hanwell J.Metabolism,excretion and pharmacokinetics of a single dose of 14C-raltitrexed in cancer patients[J].Cancer Chemother Pharmacol,1998,42:71-76.
[11]孙宾,李兴,宋杰,等.进展期胃癌术前介入治疗的临床应用[J].实用放射学杂志,2014,27:2054-2057.
[12]王良忠,李宁毅,马霖,等.氟尿嘧啶和卡铂周围静脉给药与舌动脉灌注栓塞后药动学实验研究[J].齐鲁医学杂志,2006,21:193-196.
[13]Stefanini GF,Anorati P,Biselli M,et al.Efficacy of transarterial targeted treatments on survival of patients with hepatpcellular carcinoma.An Italian experience[J].Cancer,1995,75:2427-2434.
[14]贺红杰,宋磊,赵丹懿,等.雷替曲塞联合奥沙利铂经TACE治疗不可切除肝癌患者的疗效评价[J].介入放射学杂志,2016,25:40-43.
[15]Kameyama M,Imaoka S,Fukuda I,et al.Delayed washout of intratumor blood flow is associated with good response to intraarteral chemoembolization for liver metastasis of colorectal cancer[J].Surgery,1993,114:97-101.
[16]Shigehara K,Kitagawa Y,Nakashima T,et al.Squamous cell carcinoma of the bladder:a patient treated successfully with a new combined chemotherapy regimen,intraarterial nedaplatin and pirarubicin plus intravenous methotrexate and vincristine[J].Int J CIin oncol,2006,1l:329-331.