合用沙利度胺对盐酸伊立替康药代动力学影响的研究
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摘要
伊立替康(简称CPT-11)为选择性拓扑异构酶Ⅰ抑制剂，为广谱抗癌药，是一种半合成的喜树碱衍生物，临床应用广泛。骨髓抑制和迟发型腹泻是本品主要的不良反应，尤其是迟发型腹泻，这也是限制其用药的关键因素之一。迟发型腹泻是由于伊立替康的代谢产物SN-38造成肠黏膜损害，引起肠道内离子转运异常，导致向肠腔分泌水和电解质过多而引发的；降低SN-38浓度可减轻伊立替康导致的迟发型腹泻。
沙利度胺具有抗血管形成、免疫调节及抗肿瘤作用。临床试验证实沙利度胺可以减轻本品的肠毒性，但其作用机制不明确，本课题拟对合用沙利度胺后伊立替康及其代谢物SN-38药代动力学的变化进行研究，为临床用药提供依据，并为化疗方案提供补充，以提高伊立替康治疗的安全性和有效性。
以健康雄性SD大鼠为受试对象，随机分入两个剂量组：盐酸伊立替康注射液10mg·kg~(-1)组和20mg·kg~(-1)组，每一剂量组均设一个对照组。实验组先腹腔注射沙利度胺药液20mg·kg~(-1)，0．5h后尾静脉注射盐酸伊立替康注射液；对照组先腹腔注射与沙利度胺药液同体积的二甲亚砜，0．5h后尾静脉注射盐酸伊立替康注射液。盐酸伊立替康注射液给药后0．083，0．5，1．0，2．0，4．0，6．0，8．0，10和12h采集血样。测定不同时间的血药浓度，采用DASver2．0软件拟合药动学参数，考察合用沙利度胺对伊立替康及其代谢物SN-38药代动力学的影响。
为配合盐酸伊立替康药代动力学研究，本课题建立了同时测定CPT-11及其活性代谢物SN-38的LC-MS／MS方法。方法学的建立使用ESI串联四级杆质谱仪，样品前处理为固相萃取法(SPE)，色谱柱为美国Waters公司Symmetry(?) C_(18)色谱柱(150mm×2．1mm，5μm)，采用梯度流动相：A：5mM甲酸铵(pH3．0)缓冲液，B：0．1％甲酸的甲醇。梯度洗脱程序如下：0～0．5min时间段时，A：B从70：30比例以恒定速度下降至0：100(曲线系数为6)，0．5～6．0min时间段时，维持0：100比例不变，6．0～6．5min时间段时，A：B从0：100比例以恒定速度至70：30(曲线系数为6)，6．5～10min时间段时，维持70：30比例不变。整个分析时间为10min，梯度流速恒定为0．25mL·min~(-1)，柱温为30℃，进样量10μL。数据采集采用MRM模式，CPT-11监测的母离子[M+H]~+为m／z 587．7，SN-38监测的母离子[M+H]~+为m／z 393．1。血样中CPT-11标准曲线范围为1．0～2000ng·mL~(-1)，其标准曲线相关系数r~2≥0．999；血样中SN-38标准曲线范围为0．5～100ng·mL~(-1)，其标准曲线相关系数r~2≥0．999。方法学结果能满足本品的药代动力学研究。
动物实验结果表明：两个剂量组中，腹腔注射沙利度胺后，CPT-11的C_(max)显著增加(p<0．05)，AUC_(0-t)也有增加，但20mg·kg~(-1)组的AUC_(0-t)增加没有统计学意义；SN-38的AUC_(0-t)显著减少(p<0．05)，C_(max)也有减少，但10mg·kg~(-1)组的C_(max)减少没有统计学意义。结果说明，沙利度胺可增加CPT-11的C_(max)，同时一定程度上增加其AUC_(0-t)，与此相反，沙利度胺可显著减少SN-38的AUC_(0-t)，同时一定程度上减小其C_(max)，这从药代动力学方面解释了沙利度胺预防盐酸伊立替康迟发型腹泻的作用机制。
本课题的实验结果为临床试验的实施提供了数据支持，为进行临床研究，本课题拟定了临床试验方案以供参考。
Irinotecan, a semisynthetic derivative of camptothecin, is a broad-spectrum antineoplastic agent of the topoisomerase I inhibitor class and its clinical application was widespread. Myelosuppression and delayed diarrhea are its critically adverse reactions, especially delayed diarrhea which was the most significant one of the factors why its clinical application was hindered. The intestinal mucosa was usually injured by the active metabolite SN-38, the ionic transport was abnormal in the intestinal tract, and delayed diarrhea was induced because of the excessive water and electrolytes secreted into the intestinal tract. Delayed diarrhea could be reduced if the concentration of SN-38 was decreased.
Thalidomide with antiangiopoiesis and immunoloregulation properties has been demonstrated antineoplastic activity. It has been confirmed that irinotecan intestinal toxicity was relieved by co-administrated thalidomide in several clinical trials. However, the mechanisms are unknown. To provide the evidence for clinical medication and to perfect the chemotherapy to insure the safety and efficacy of irinotecan, the study should be established to investigate the interaction between irinotecan and thalidomide.
Healthy male Sprague Dawley rats were randomized to two groups with one group receiving CPT-11 at 10mg·kg~(-1) by i.v. and the other group receiving CPT-11 at 20mg·kg~(-1) by i.v., both groups in combination with thalidomide (20mg·kg~(-1) by i.p. given 30min prior to CPT-11 injection). Either of the two doses has a control group which is administrated the same dose CPT-11 in combination with DMSO whose administration is the same as thalidomide. Blood samples were collected at 0.083, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10 and 12h following CPT-11 injection. The plasma concentrations were determined and pharmacokinetics parameters were fitted to inspect the change of pharmacokinetics of both CPT-11 and SN-38 by the DASver2.0 software.
To support the study of pharmacokinetics of irinotecan, a LC-MS/MS method was established for simultaneous determination of CPT-11 and its active metabolite SN-38. The ESI tandem quadrupole mass spectrometer was used in the methodology of biopharmaceutical analysis. Solid phase extraction was utilized for the sample preparation. The gradient mobile phase was consisted of 5mM ammonium formiate solution pH3.0 (A) and 0.1%formic acid in methanol (B). The gradient process was shown below. During 0-0.5min, the ratio of A:B stepped from 70:30 to 0:100. During 0.5-6min, the ratio of A:B sustained at 0:100. During 6-6.5min, the ratio of A:B stepped from 0:100 to 70:30. During 6.5-10min, the ratio of A:B sustained at 70:30. The total time of the analysis was 10min, the flow rate was 0.25mL·min~(-1) and the column temperature was 30℃. The MRM mode was used in the data acquiring. The parent ion of CPT-11 was m/z 587.7 [M+H]~+, the linear range of standard curve of plasma sample was 1.0-2000ng·mL~(-1), and the r~2≥0.999. The parent ion of SN38 was m/z 393.1[M+H]~+, the linear range of standard curve of plasma sample was 0.5-100ng·mL~(-1), and the r~2≥0.999. This method was applied to the study suitably.
Between the both doses combined with thalidomide by i.p., the C_(max) of CPT-11 was increased significantly (p<0.05) of both doses, its AUC_(0-t) was increased in both groups, but AUC_(20mg·kg~(-1)) was increased without statistical significance, the AUC_(0-t) of SN38 was decreased significantly (p<0.05) of both doses, its C_(max) was decreased in both groups, but its C_(max) of the dose of 10 mg·kg~(-1) was decreased without statistical significance. The results of pharmacokinetics in rats indicated that co-administrated thalidomide could increase the C_(max) significantly (p<0.05) and the AUC_(0-t) of CPT-11 to some extent and attenuate the AUC_(0-t) significantly (p<0.05) and the C_(max) of SN-38 to some extent. The pharmacokinetic study revealed the mechanism of action that the delayed diarrhea of irinotecan could be prevented by thalidomide.
The experimental results provides reasonable data for clinical trial. To put the clinical trial in progress, the protocol was layinged to provide references in the study.
沙利度胺具有抗血管形成、免疫调节及抗肿瘤作用。临床试验证实沙利度胺可以减轻本品的肠毒性，但其作用机制不明确，本课题拟对合用沙利度胺后伊立替康及其代谢物SN-38药代动力学的变化进行研究，为临床用药提供依据，并为化疗方案提供补充，以提高伊立替康治疗的安全性和有效性。
以健康雄性SD大鼠为受试对象，随机分入两个剂量组：盐酸伊立替康注射液10mg·kg~(-1)组和20mg·kg~(-1)组，每一剂量组均设一个对照组。实验组先腹腔注射沙利度胺药液20mg·kg~(-1)，0．5h后尾静脉注射盐酸伊立替康注射液；对照组先腹腔注射与沙利度胺药液同体积的二甲亚砜，0．5h后尾静脉注射盐酸伊立替康注射液。盐酸伊立替康注射液给药后0．083，0．5，1．0，2．0，4．0，6．0，8．0，10和12h采集血样。测定不同时间的血药浓度，采用DASver2．0软件拟合药动学参数，考察合用沙利度胺对伊立替康及其代谢物SN-38药代动力学的影响。
为配合盐酸伊立替康药代动力学研究，本课题建立了同时测定CPT-11及其活性代谢物SN-38的LC-MS／MS方法。方法学的建立使用ESI串联四级杆质谱仪，样品前处理为固相萃取法(SPE)，色谱柱为美国Waters公司Symmetry(?) C_(18)色谱柱(150mm×2．1mm，5μm)，采用梯度流动相：A：5mM甲酸铵(pH3．0)缓冲液，B：0．1％甲酸的甲醇。梯度洗脱程序如下：0～0．5min时间段时，A：B从70：30比例以恒定速度下降至0：100(曲线系数为6)，0．5～6．0min时间段时，维持0：100比例不变，6．0～6．5min时间段时，A：B从0：100比例以恒定速度至70：30(曲线系数为6)，6．5～10min时间段时，维持70：30比例不变。整个分析时间为10min，梯度流速恒定为0．25mL·min~(-1)，柱温为30℃，进样量10μL。数据采集采用MRM模式，CPT-11监测的母离子[M+H]~+为m／z 587．7，SN-38监测的母离子[M+H]~+为m／z 393．1。血样中CPT-11标准曲线范围为1．0～2000ng·mL~(-1)，其标准曲线相关系数r~2≥0．999；血样中SN-38标准曲线范围为0．5～100ng·mL~(-1)，其标准曲线相关系数r~2≥0．999。方法学结果能满足本品的药代动力学研究。
动物实验结果表明：两个剂量组中，腹腔注射沙利度胺后，CPT-11的C_(max)显著增加(p<0．05)，AUC_(0-t)也有增加，但20mg·kg~(-1)组的AUC_(0-t)增加没有统计学意义；SN-38的AUC_(0-t)显著减少(p<0．05)，C_(max)也有减少，但10mg·kg~(-1)组的C_(max)减少没有统计学意义。结果说明，沙利度胺可增加CPT-11的C_(max)，同时一定程度上增加其AUC_(0-t)，与此相反，沙利度胺可显著减少SN-38的AUC_(0-t)，同时一定程度上减小其C_(max)，这从药代动力学方面解释了沙利度胺预防盐酸伊立替康迟发型腹泻的作用机制。
本课题的实验结果为临床试验的实施提供了数据支持，为进行临床研究，本课题拟定了临床试验方案以供参考。
Irinotecan, a semisynthetic derivative of camptothecin, is a broad-spectrum antineoplastic agent of the topoisomerase I inhibitor class and its clinical application was widespread. Myelosuppression and delayed diarrhea are its critically adverse reactions, especially delayed diarrhea which was the most significant one of the factors why its clinical application was hindered. The intestinal mucosa was usually injured by the active metabolite SN-38, the ionic transport was abnormal in the intestinal tract, and delayed diarrhea was induced because of the excessive water and electrolytes secreted into the intestinal tract. Delayed diarrhea could be reduced if the concentration of SN-38 was decreased.
Thalidomide with antiangiopoiesis and immunoloregulation properties has been demonstrated antineoplastic activity. It has been confirmed that irinotecan intestinal toxicity was relieved by co-administrated thalidomide in several clinical trials. However, the mechanisms are unknown. To provide the evidence for clinical medication and to perfect the chemotherapy to insure the safety and efficacy of irinotecan, the study should be established to investigate the interaction between irinotecan and thalidomide.
Healthy male Sprague Dawley rats were randomized to two groups with one group receiving CPT-11 at 10mg·kg~(-1) by i.v. and the other group receiving CPT-11 at 20mg·kg~(-1) by i.v., both groups in combination with thalidomide (20mg·kg~(-1) by i.p. given 30min prior to CPT-11 injection). Either of the two doses has a control group which is administrated the same dose CPT-11 in combination with DMSO whose administration is the same as thalidomide. Blood samples were collected at 0.083, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10 and 12h following CPT-11 injection. The plasma concentrations were determined and pharmacokinetics parameters were fitted to inspect the change of pharmacokinetics of both CPT-11 and SN-38 by the DASver2.0 software.
To support the study of pharmacokinetics of irinotecan, a LC-MS/MS method was established for simultaneous determination of CPT-11 and its active metabolite SN-38. The ESI tandem quadrupole mass spectrometer was used in the methodology of biopharmaceutical analysis. Solid phase extraction was utilized for the sample preparation. The gradient mobile phase was consisted of 5mM ammonium formiate solution pH3.0 (A) and 0.1%formic acid in methanol (B). The gradient process was shown below. During 0-0.5min, the ratio of A:B stepped from 70:30 to 0:100. During 0.5-6min, the ratio of A:B sustained at 0:100. During 6-6.5min, the ratio of A:B stepped from 0:100 to 70:30. During 6.5-10min, the ratio of A:B sustained at 70:30. The total time of the analysis was 10min, the flow rate was 0.25mL·min~(-1) and the column temperature was 30℃. The MRM mode was used in the data acquiring. The parent ion of CPT-11 was m/z 587.7 [M+H]~+, the linear range of standard curve of plasma sample was 1.0-2000ng·mL~(-1), and the r~2≥0.999. The parent ion of SN38 was m/z 393.1[M+H]~+, the linear range of standard curve of plasma sample was 0.5-100ng·mL~(-1), and the r~2≥0.999. This method was applied to the study suitably.
Between the both doses combined with thalidomide by i.p., the C_(max) of CPT-11 was increased significantly (p<0.05) of both doses, its AUC_(0-t) was increased in both groups, but AUC_(20mg·kg~(-1)) was increased without statistical significance, the AUC_(0-t) of SN38 was decreased significantly (p<0.05) of both doses, its C_(max) was decreased in both groups, but its C_(max) of the dose of 10 mg·kg~(-1) was decreased without statistical significance. The results of pharmacokinetics in rats indicated that co-administrated thalidomide could increase the C_(max) significantly (p<0.05) and the AUC_(0-t) of CPT-11 to some extent and attenuate the AUC_(0-t) significantly (p<0.05) and the C_(max) of SN-38 to some extent. The pharmacokinetic study revealed the mechanism of action that the delayed diarrhea of irinotecan could be prevented by thalidomide.
The experimental results provides reasonable data for clinical trial. To put the clinical trial in progress, the protocol was layinged to provide references in the study.
引文
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44. Kitagawa C, Ando M, Ando Y, et al. Genetic polymorphisms of the multidrug resistance-associated protein 2 gene (ABCC2) and irinotecan toxicity[C]. J Clin Oncol. Annual Meeting Proceedings (Post-Meeting Edition). 2003, 22.
45. De Jong FA, Marsh S, Mathijssen RH, et al. ABCG2 pharmacogenetics: ethnic differences in allele frequency and assessment of influence on irinotecan disposition[J]. Clin Cancer Res. 2004, 10(17): 5889-5894.
46. Gandia D, Abigerges D, Armand JP, et al. CPT-11-induced cholinergic effects in cancer patients[J]. J Clin Oncol. 1993, 11(1): 196-197.
47. Kurita A, Kado S, Kaneda N, et al. Moditied irinotecan hydrochloride (CPT-11) administration schedule improves induction of delayed-onsetdiarrhea in rats[J]. Cancer Chemother Pharmacol. 2000, 46(3): 211-220.
48. Masi G, Allegrini G, Cupini S, et al. First-line treatment df metastatic colorectal cancer with irinotecan, oxaliplatin and 5-fluorouracil/leucdvorin (FOLFOXIRI) [J]. Ann Oncol. 2004, 15(12): 1766-1772.
49. Pro B, Lozano R, Ajani JA. Therapeutic response to octreotide in patients with
??refractory CPT-11 induced diarrhea[J].Invest New DRugs. 2001, 19(4): 341-343.
50．卢惠明．开普拓治疗晚期大肠癌的护理[J]．南方护理学报，2002，9(2)：51-52．
51.Camptosar(?) irinotecan hydrochloride injection[EB/OL]. 2006[2007-05-12]. http://www.fda.gov/cder/foi/label/2006/020571s030lbl.pdf.
52. Invader UGT1A1 molecular assay for irinotecan toxicity. A genetic test for an increased risk of toxicity from the cancer chemotherapy drug irinotecan (Camptosar) [J]. Med Lett Drugs Ther. 2006, 48(1234): 39-40.
53. Ando M, Hasegawa Y, Ando Y. Pharmacogenetics of irinotecan: a promoter polymorphism of UGT1A1 gene and severe adverse reactions to irinotecan[J]. Invest New Drugs. 2005, 23(6): 539-545.
54. Sehmittel A, Jahnke K, Thiel E, et al. Neomycin as secondary prophylaxis for irinotecan-induced diarrhea[J].Ann Oncol. 2004, 15(8): 1296-1296.
55. Wadkins RM, Hyatt JL, Yoon KJ, et al. Discovery of novel selective inhibitors of human intestinal carboxylesterase for the amelioration of irinotecan-induced diarrhea: synthesis, quantitative structure-activity relationship analysis,and biological activity[J]. Mol Pharmacol. 2004, 65(6): 1336-1343.
56. Kobayashi K, Bouscarel B, Matsuzaki Y, et al. pH-dependent uptake of irinotecan and its active metabolite, SN-38, by intestinal cells[J]. Int J Cancer. 1999; 83(4): 491-496.
57. Akimota K, Kawai A, Ohva K. Kinetic studies of the hydrolysis and lactonization of camptothecin and its derivatives, CPT-11 and SN-38, in aqueous solution[J]. Chem Pharm Bull. 1994,42(10): 2135-2138.
58. Takeda Y, Kobayashi K, Akiyama Y, et al. Prevention of irinotecan (CPT-11)-induced diarrhea by oral alkalization combined with control of defecation in cancer patients[J]. Int J Cancer. 2001, 92(2): 269-275.
59. Michael M, Brittain M, Nagai J, et al. Phase Ⅱ study of activated charcoal to prevent irinotecan-induced diarrhea[J]. J Clin Oncol. 2004, 22(21): 4410-4417.
60. MaedaY, OhuneT, Nakamure M, et al. Prevention of irinotecan-induced diarrhoea by oral carbonaceous adsorbent (Kremezin) in cancer patients[J]. Oncol Rep. 2004, 12(3): 581-585.
61. Takeda Y, Kobayashi K, Akiyama Y, et al. Prevention of irinotecan (CPT-11)-induced diarrhea by oral alkalization combined with control of defecation in cancer patients[J]. Int J Cancer. 2001,92(2): 269-275.
62. Trifan OC, Durham WF, Salazar VS, et al. Cyclooxygenase-2 inhibition with celecoxib enhances antitumor efficacy and reduces diarrhea side effect of CPT-11[J]. Cancer Res. 2002,62(20): 5778-5784.
63. Reardon DA, Quinn JA, Vredenburgh J, et al. Phase II trial of irinotecan plus celecoxib in adults with recurrent malignant glioma[J]. Cancer. 2004, 103(2): 329-338.
64. Innocenti F, Undevia SD, Ramirez J, et al. A phase I trial of pharmacologic modulation of irinotecan with cyclosporine and phenobarbital[J]. Clin Pharmacol Ther. 2004, 76(5): 490-502.
65. Arimori K, Kuroki N, Hidaka M, et al. Effect of P-glycoprotein modulator, cyclosporin A, on the gastrointestinal excretion of irinotecan and its metabolite SN-38 in rats[J]. Pharm Res. 2003, 20(6): 910-917.
66. Chowbay B, Sharma A, Zhou QY, et al. The modulation of irinotecan-induced diarrhoea and pharmacokinetics by three different classes of pharmacologic agents[J]. Oncol Rep. 2003, 10(3): 745-751.
67. Mori K, Kondo T, Kamiyama Y, et al. Preventive effect of Kampo medicine (Hangeshashinto) against irinotecan-induced diarrhea in advanced non-small-cell lung cancer[J]. Cancer Chemother Pharmacol. 2003, 51(5): 403-406.
68. Ikegami T, Ha L, Arimori K, et al. Intestinal alkalization as a possible preventive mechanism in irinotecan (CPT-11)-induced diarrhea[J]. Cancer Res. 2002, 62(1): 179-187.
69. Rviory LP, Chatelut E, Canal P, et al. Kinetics of the in vivo interconversion of the carboxate and lactone forms of irniotecan(CPT-11) and of its metabolite SN-38 in pateints[J]. Cancer Res. 1994, 54(24): 6330-6333.
70. Yasutsuna S, Yasushi Y, Kenichi S, et al. Pharmacologcial correlation between total drug concentration and lactones of CPT-11 and SN-38 in patients treated with CPT-11 [J]. Jpn J Cancer Res. 1995, 86(1): 111-116.
71. Yang XX, Hu ZP, Chan SY, et al. Simultaneous determination of the lactone and carboxylate formsof irinotecan (CPT-11)and its active metabolite SN-38 by high-performance liquid chomatography: Application to plasma pharmacokinetic studies in the rat[J]. Journal of Chomatography B. 2005, 821(2): 221-228.
72. Khan S, Ahmad A, Guo W, et al. A simple and sensitive LC/MS/MS assay for 7-ethyl-10-hydroxycamptothecin (SN-38) in mouse plasma and tissues: application to pharmacokinetic study of liposome entrapped SN-38(LE-SN-38)[J]. Journal of Pharmaceutical and Biomedical Analysis. 2005,37(1): 135-142.
73. Hu ZP, Yang XX, Chen X, et al. Simultaneous determination of irinotecan (CPT-11)and SN-38 in tissue culture media and cancer cells by high performance liquid chomatography: Application to cellular metabolism and accumulation studies [J]. Journal of Chomatography B, 2007, 850(1-2): 575-580.
74. Muck W. Quantitative analysis of pharmacokinetic study samples by liquid chomatography coupled to tandem mass spectrometry(LC-MS/MS)[J]. Pharmazie. 1999, 54(9): 639-644.
75. Kostiainen R, Kotiaho T, Kuuranne T, et al. Liquid chomatography/ atmospheric pressure ionization-mass spectrometry in drug metabolism studies[J]. J Mass Spectrom. 2003, 38(4): 357-372.
76. Hsieh Y, Fukuda E, Wingate J, et al. Fast mass spectrometry-based methodologies for pharmaceutical analyses[J]. Comb Chem High Thoughput Screen. 2006, 9(1): 3-8.
77．王丽焱，汤致强，徐驰．人血清中伊立替康的液质联用测定方法[J]． 中国药学杂志．2005，40(1)：58-60．
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42. Sai K, Kaniwa N, Itoda M, et al. Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan[J]. Pharmacogenetics. 2003, 13(12): 741-757.
43. Innocenti F, Undevia SD, Chen PX, et al. Pharmacogenetic analysis of interindividual irinotecan (CPT-11) pharmacokinetic (PK) variability: evidence for a functional variant of ABCC2[C]. J Clin Oncol. Annual Meeting Proceedings (Post-Meeting Edition). 2004, 22.
44. Kitagawa C, Ando M, Ando Y, et al. Genetic polymorphisms of the multidrug resistance-associated protein 2 gene (ABCC2) and irinotecan toxicity[C]. J Clin Oncol. Annual Meeting Proceedings (Post-Meeting Edition). 2003, 22.
45. De Jong FA, Marsh S, Mathijssen RH, et al. ABCG2 pharmacogenetics: ethnic differences in allele frequency and assessment of influence on irinotecan disposition[J]. Clin Cancer Res. 2004, 10(17): 5889-5894.
46. Gandia D, Abigerges D, Armand JP, et al. CPT-11-induced cholinergic effects in cancer patients[J]. J Clin Oncol. 1993, 11(1): 196-197.
47. Kurita A, Kado S, Kaneda N, et al. Moditied irinotecan hydrochloride (CPT-11) administration schedule improves induction of delayed-onsetdiarrhea in rats[J]. Cancer Chemother Pharmacol. 2000, 46(3): 211-220.
48. Masi G, Allegrini G, Cupini S, et al. First-line treatment df metastatic colorectal cancer with irinotecan, oxaliplatin and 5-fluorouracil/leucdvorin (FOLFOXIRI) [J]. Ann Oncol. 2004, 15(12): 1766-1772.
49. Pro B, Lozano R, Ajani JA. Therapeutic response to octreotide in patients with
??refractory CPT-11 induced diarrhea[J].Invest New DRugs. 2001, 19(4): 341-343.
50．卢惠明．开普拓治疗晚期大肠癌的护理[J]．南方护理学报，2002，9(2)：51-52．
51.Camptosar(?) irinotecan hydrochloride injection[EB/OL]. 2006[2007-05-12]. http://www.fda.gov/cder/foi/label/2006/020571s030lbl.pdf.
52. Invader UGT1A1 molecular assay for irinotecan toxicity. A genetic test for an increased risk of toxicity from the cancer chemotherapy drug irinotecan (Camptosar) [J]. Med Lett Drugs Ther. 2006, 48(1234): 39-40.
53. Ando M, Hasegawa Y, Ando Y. Pharmacogenetics of irinotecan: a promoter polymorphism of UGT1A1 gene and severe adverse reactions to irinotecan[J]. Invest New Drugs. 2005, 23(6): 539-545.
54. Sehmittel A, Jahnke K, Thiel E, et al. Neomycin as secondary prophylaxis for irinotecan-induced diarrhea[J].Ann Oncol. 2004, 15(8): 1296-1296.
55. Wadkins RM, Hyatt JL, Yoon KJ, et al. Discovery of novel selective inhibitors of human intestinal carboxylesterase for the amelioration of irinotecan-induced diarrhea: synthesis, quantitative structure-activity relationship analysis,and biological activity[J]. Mol Pharmacol. 2004, 65(6): 1336-1343.
56. Kobayashi K, Bouscarel B, Matsuzaki Y, et al. pH-dependent uptake of irinotecan and its active metabolite, SN-38, by intestinal cells[J]. Int J Cancer. 1999; 83(4): 491-496.
57. Akimota K, Kawai A, Ohva K. Kinetic studies of the hydrolysis and lactonization of camptothecin and its derivatives, CPT-11 and SN-38, in aqueous solution[J]. Chem Pharm Bull. 1994,42(10): 2135-2138.
58. Takeda Y, Kobayashi K, Akiyama Y, et al. Prevention of irinotecan (CPT-11)-induced diarrhea by oral alkalization combined with control of defecation in cancer patients[J]. Int J Cancer. 2001, 92(2): 269-275.
59. Michael M, Brittain M, Nagai J, et al. Phase Ⅱ study of activated charcoal to prevent irinotecan-induced diarrhea[J]. J Clin Oncol. 2004, 22(21): 4410-4417.
60. MaedaY, OhuneT, Nakamure M, et al. Prevention of irinotecan-induced diarrhoea by oral carbonaceous adsorbent (Kremezin) in cancer patients[J]. Oncol Rep. 2004, 12(3): 581-585.
61. Takeda Y, Kobayashi K, Akiyama Y, et al. Prevention of irinotecan (CPT-11)-induced diarrhea by oral alkalization combined with control of defecation in cancer patients[J]. Int J Cancer. 2001,92(2): 269-275.
62. Trifan OC, Durham WF, Salazar VS, et al. Cyclooxygenase-2 inhibition with celecoxib enhances antitumor efficacy and reduces diarrhea side effect of CPT-11[J]. Cancer Res. 2002,62(20): 5778-5784.
63. Reardon DA, Quinn JA, Vredenburgh J, et al. Phase II trial of irinotecan plus celecoxib in adults with recurrent malignant glioma[J]. Cancer. 2004, 103(2): 329-338.
64. Innocenti F, Undevia SD, Ramirez J, et al. A phase I trial of pharmacologic modulation of irinotecan with cyclosporine and phenobarbital[J]. Clin Pharmacol Ther. 2004, 76(5): 490-502.
65. Arimori K, Kuroki N, Hidaka M, et al. Effect of P-glycoprotein modulator, cyclosporin A, on the gastrointestinal excretion of irinotecan and its metabolite SN-38 in rats[J]. Pharm Res. 2003, 20(6): 910-917.
66. Chowbay B, Sharma A, Zhou QY, et al. The modulation of irinotecan-induced diarrhoea and pharmacokinetics by three different classes of pharmacologic agents[J]. Oncol Rep. 2003, 10(3): 745-751.
67. Mori K, Kondo T, Kamiyama Y, et al. Preventive effect of Kampo medicine (Hangeshashinto) against irinotecan-induced diarrhea in advanced non-small-cell lung cancer[J]. Cancer Chemother Pharmacol. 2003, 51(5): 403-406.
68. Ikegami T, Ha L, Arimori K, et al. Intestinal alkalization as a possible preventive mechanism in irinotecan (CPT-11)-induced diarrhea[J]. Cancer Res. 2002, 62(1): 179-187.
69. Rviory LP, Chatelut E, Canal P, et al. Kinetics of the in vivo interconversion of the carboxate and lactone forms of irniotecan(CPT-11) and of its metabolite SN-38 in pateints[J]. Cancer Res. 1994, 54(24): 6330-6333.
70. Yasutsuna S, Yasushi Y, Kenichi S, et al. Pharmacologcial correlation between total drug concentration and lactones of CPT-11 and SN-38 in patients treated with CPT-11 [J]. Jpn J Cancer Res. 1995, 86(1): 111-116.
71. Yang XX, Hu ZP, Chan SY, et al. Simultaneous determination of the lactone and carboxylate formsof irinotecan (CPT-11)and its active metabolite SN-38 by high-performance liquid chomatography: Application to plasma pharmacokinetic studies in the rat[J]. Journal of Chomatography B. 2005, 821(2): 221-228.
72. Khan S, Ahmad A, Guo W, et al. A simple and sensitive LC/MS/MS assay for 7-ethyl-10-hydroxycamptothecin (SN-38) in mouse plasma and tissues: application to pharmacokinetic study of liposome entrapped SN-38(LE-SN-38)[J]. Journal of Pharmaceutical and Biomedical Analysis. 2005,37(1): 135-142.
73. Hu ZP, Yang XX, Chen X, et al. Simultaneous determination of irinotecan (CPT-11)and SN-38 in tissue culture media and cancer cells by high performance liquid chomatography: Application to cellular metabolism and accumulation studies [J]. Journal of Chomatography B, 2007, 850(1-2): 575-580.
74. Muck W. Quantitative analysis of pharmacokinetic study samples by liquid chomatography coupled to tandem mass spectrometry(LC-MS/MS)[J]. Pharmazie. 1999, 54(9): 639-644.
75. Kostiainen R, Kotiaho T, Kuuranne T, et al. Liquid chomatography/ atmospheric pressure ionization-mass spectrometry in drug metabolism studies[J]. J Mass Spectrom. 2003, 38(4): 357-372.
76. Hsieh Y, Fukuda E, Wingate J, et al. Fast mass spectrometry-based methodologies for pharmaceutical analyses[J]. Comb Chem High Thoughput Screen. 2006, 9(1): 3-8.
77．王丽焱，汤致强，徐驰．人血清中伊立替康的液质联用测定方法[J]． 中国药学杂志．2005，40(1)：58-60．
78. Gupta E, Lestingi TM, Mick R, et al. Metabolic fate of irinotecan in humansxorrelation of glucuronidation with diarrhea[J]. Cancer Res. 1994, 54(14): 3723-3725.