甲氧基喜树碱的药代动力学研究
|
摘要
喜树碱(CPT)是20世纪60年代从珙桐科植物喜树中提取的天然生物碱,由于具有显著的抗癌活性,得到了广泛的重视。甲氧基喜树碱(MCPT)和羟基喜树碱(HCPT)均是喜树碱的天然衍生物,并具有较强的抗肿瘤活性。HCPT是我国临床应用的抗肿瘤药物,在药效学以及药剂学方面均有广泛的研究。关于MCPT的研究并不多见,这可能是由于MCPT较强的毒性所致。在我们的研究中发现,HCPT是MCPT的-种主要代谢产物,这激发了我们进一步研究MCPT的兴趣。在本文中我们研究了MCPT的细胞毒活性及其与细胞转运载体之间的相互作用,并进一步对MCPT及其代谢产物HCPT在大鼠血浆的药代动力学、组织分布特征以及排泄规律进行了研究。
为了初步确定MCPT的抗肿瘤活性,以CPT和HCPT为对照,研究了MCPT对人卵巢癌细胞2774、结肠癌细胞系HT29.前列腺癌细胞系DU145、肺癌细胞系NCI-H520以及人胰腺癌细胞系MPC2的体外细胞毒活性。结果表明,MCPT在所测试的所有细胞系中的细胞毒活性均高于HCPT;除HT29外,MCPT在其他细胞系中均表现出比CPT更强的细胞毒活性。
考察了CPT、MCPT和HCPT与多种转运蛋白的相互作用,发现这三种物质均能够有效抑制有机阴离子转运蛋白3(OAT3)的转运功能。这说明,这三种物质有可能是OAT3的底物。另外,由于OAT3主要分布于肾脏中,在肾脏毒素的排除中起到重要作用,这有可能是喜树碱类容易产生肾脏毒性的一个原因。
利用HPLC-PDA和LC-MS/MS的方法确证了HCPT为MCPT的代谢产物,并建立了一种灵敏的、可靠的同时检测大鼠血浆中MCPT及其代谢产物HCPT的高效液相色谱-荧光检测的方法。
考察了大鼠尾静脉注射5mg/kg MCPT后,MCPT及其主要代谢产物HCPT在血浆中药代动力学。尾静脉注射MCPT后,MCPT立刻达到最高浓度,随后浓度很快降低；而HCPT在5-10min后达到最高浓度,且明显高于MCPT,HCPT的药时曲线下面积约为MCPT的1.5倍,说明MCPT主要通过去甲基化作用代谢为HCPT。
考察了大鼠尾静脉注射5mg/kg MCPT后,MCPT及其主要代谢产物HCPT在大鼠各组织中的分布情况。结果表明,肝脏、脾脏和肾脏中MCPT的含量较高,而在脑中的含量最少；而对于HCPT,在肝脏和肾脏中的含量最高,其他组织中的含量略少。
比较分析了大鼠尾静脉注射MCPT后,MCPT及其代谢产物HCPT在胆汁、尿液和粪便中的排泄特征。结果表明,MCPT主要以胆汁的形式排出体外,而HCPT则主要以粪便的形式排除体外。
本文对MCPT及其代谢产物HCPT在大鼠体内的药代动力学进行了研究,明确了MCPT和HCPT在大鼠体内的吸收、分布、代谢和排泄的规律,为MCPT的临床应用及合理开发提供了一定的理论依据。
Camptothecin (CPT) is a naturally occurring alkaloid first isolated from the native Chinese tree Camptotheca acuminate Dence.(Nyssaceae) in1960s. CPT has been paid considerable attention because of its significant anti-tumor activity. Both10-methoxycamptothecin and10-hydroxycamptothecin are natural bioactive derivatives of camptothecin and have been confirmed to possess high anti-cancer properties. The reduced toxicity of HCPT campared to CPT has brought the growing interesting of in vivo and clinical studies on the pharmaceutics and pharmacology of HCPT. In contrast, few studies were carried out on MCPT due to its higher toxicity. Later, HCPT was found to be one of the major metabolites of MCPT metabolites in rat pasma after intravenous administration of MCPT, which brings new interest to the potential use of MCPT in the development of novel anticancer drugs. In the present study, the antitumor activity of MCPT against five different cancer cells as well as the interaction of MCPT, HCPT and CPT with solute carrier transporters was tested here. Further the pharmacokinetic studies, the tissue distribution studies as well as the excretion studies of MCPT and its metabolite HCPT were demonstrated.
To elucidate the potential activity of MCPT, we tested its antitumor activity against five cancer cell lines, including2774(human ovarian cancer cell line), HT29(human colon cancer cell line), DU145(human prostate carcinoma cell line), NCI-H520(human lung cancer cell line) and MPC2(mice pancreatic cancer cell line), compared with CPT and HCPT. The results indicated that MCPT has higher anticancer activities against all the tested cancer cell lines comparted with HCPT, and showed higher anticancer acticities aganist all the tested cancer cell lines except nearly the same cytotoxicity against HT29cell line.
In order to elucidate the contribution of solute carrier (SLC) transporters to the efficacy and toxicity of CPT, MCPT and HCPT, this study investigated the interactions of these compounds with thirteen essential SLC transporters, and our data revealed that they all significantly inhibited the function of OAT3, which implied that these three CPTs might be the potential substrates of OATs. This might be a possible reason of the kidney toxicity of CPTs because OAT3is expressed at the basolateral membranes of the renal proximal tubule where it facilated the first step in the clearance of uremic toxins.
HCPT was identified as the major metabolite of MCPT in rat plasma through HPLC/photodiode array detection (PDA) and LC-MS/MS analysis. A sensitive and reliable RP-HPLC method with fluorescence detection was developed and validated for the simultaneous analysis of MCPT and HCPT in rat plasma. This method was also applied to the pharmacokinetic study of MCPT and its metabolite HCPT in rat plasma after intravenous administration.
In this study, the mean plasma concentration-time curves of MCPT and its metabolite HCPT were determined for six rats each receiving a single5mg/kg i.v. dose of MCPT via the tail vein. After i.v. administration, the level of MCPT reached the maximum concentration, and declined immediately. HCPT concentration reached the maximum within the first5-10min post-administration of the dose, and after that HCPT level declined promptly.. The ratio of AUC0-∞of HCPT to that of MCPT was about150%, which demonstrated that the metabolism to the demethylated HCPT was the dominant metabolic reaction for MCPT in rats.
The tissue distribution of MCPT and its metabolite HCPT were determined for rats after each receiving a single5mg/kg i.v. dose of MCPT via the tail vein. These results indicated that the content of MCPT was higher in liver, spleen and kidney, and was lowest in brain, while the content of HCPT was higher in liver and kidney than in other tissues.
At last, the accumulation of MCPT and and its metabolite HCPT in excretion pathway was investigated after receiving a single5mg/kg i.v. dose of MCPT via the tail vein. The results indicated that MCPT was excreted in bile mostly, while HCPT was mainly excreted in feces.
In summary, a pharmacokinetic study of MCPT and and its metabolite HCPT in rats were investigated, and the absorption, distribution, metabolism, excretion of MCPT was clarified, in order to provide a theories basis for the clinical medication, reasonable development and application of MCPT.
为了初步确定MCPT的抗肿瘤活性,以CPT和HCPT为对照,研究了MCPT对人卵巢癌细胞2774、结肠癌细胞系HT29.前列腺癌细胞系DU145、肺癌细胞系NCI-H520以及人胰腺癌细胞系MPC2的体外细胞毒活性。结果表明,MCPT在所测试的所有细胞系中的细胞毒活性均高于HCPT;除HT29外,MCPT在其他细胞系中均表现出比CPT更强的细胞毒活性。
考察了CPT、MCPT和HCPT与多种转运蛋白的相互作用,发现这三种物质均能够有效抑制有机阴离子转运蛋白3(OAT3)的转运功能。这说明,这三种物质有可能是OAT3的底物。另外,由于OAT3主要分布于肾脏中,在肾脏毒素的排除中起到重要作用,这有可能是喜树碱类容易产生肾脏毒性的一个原因。
利用HPLC-PDA和LC-MS/MS的方法确证了HCPT为MCPT的代谢产物,并建立了一种灵敏的、可靠的同时检测大鼠血浆中MCPT及其代谢产物HCPT的高效液相色谱-荧光检测的方法。
考察了大鼠尾静脉注射5mg/kg MCPT后,MCPT及其主要代谢产物HCPT在血浆中药代动力学。尾静脉注射MCPT后,MCPT立刻达到最高浓度,随后浓度很快降低；而HCPT在5-10min后达到最高浓度,且明显高于MCPT,HCPT的药时曲线下面积约为MCPT的1.5倍,说明MCPT主要通过去甲基化作用代谢为HCPT。
考察了大鼠尾静脉注射5mg/kg MCPT后,MCPT及其主要代谢产物HCPT在大鼠各组织中的分布情况。结果表明,肝脏、脾脏和肾脏中MCPT的含量较高,而在脑中的含量最少；而对于HCPT,在肝脏和肾脏中的含量最高,其他组织中的含量略少。
比较分析了大鼠尾静脉注射MCPT后,MCPT及其代谢产物HCPT在胆汁、尿液和粪便中的排泄特征。结果表明,MCPT主要以胆汁的形式排出体外,而HCPT则主要以粪便的形式排除体外。
本文对MCPT及其代谢产物HCPT在大鼠体内的药代动力学进行了研究,明确了MCPT和HCPT在大鼠体内的吸收、分布、代谢和排泄的规律,为MCPT的临床应用及合理开发提供了一定的理论依据。
Camptothecin (CPT) is a naturally occurring alkaloid first isolated from the native Chinese tree Camptotheca acuminate Dence.(Nyssaceae) in1960s. CPT has been paid considerable attention because of its significant anti-tumor activity. Both10-methoxycamptothecin and10-hydroxycamptothecin are natural bioactive derivatives of camptothecin and have been confirmed to possess high anti-cancer properties. The reduced toxicity of HCPT campared to CPT has brought the growing interesting of in vivo and clinical studies on the pharmaceutics and pharmacology of HCPT. In contrast, few studies were carried out on MCPT due to its higher toxicity. Later, HCPT was found to be one of the major metabolites of MCPT metabolites in rat pasma after intravenous administration of MCPT, which brings new interest to the potential use of MCPT in the development of novel anticancer drugs. In the present study, the antitumor activity of MCPT against five different cancer cells as well as the interaction of MCPT, HCPT and CPT with solute carrier transporters was tested here. Further the pharmacokinetic studies, the tissue distribution studies as well as the excretion studies of MCPT and its metabolite HCPT were demonstrated.
To elucidate the potential activity of MCPT, we tested its antitumor activity against five cancer cell lines, including2774(human ovarian cancer cell line), HT29(human colon cancer cell line), DU145(human prostate carcinoma cell line), NCI-H520(human lung cancer cell line) and MPC2(mice pancreatic cancer cell line), compared with CPT and HCPT. The results indicated that MCPT has higher anticancer activities against all the tested cancer cell lines comparted with HCPT, and showed higher anticancer acticities aganist all the tested cancer cell lines except nearly the same cytotoxicity against HT29cell line.
In order to elucidate the contribution of solute carrier (SLC) transporters to the efficacy and toxicity of CPT, MCPT and HCPT, this study investigated the interactions of these compounds with thirteen essential SLC transporters, and our data revealed that they all significantly inhibited the function of OAT3, which implied that these three CPTs might be the potential substrates of OATs. This might be a possible reason of the kidney toxicity of CPTs because OAT3is expressed at the basolateral membranes of the renal proximal tubule where it facilated the first step in the clearance of uremic toxins.
HCPT was identified as the major metabolite of MCPT in rat plasma through HPLC/photodiode array detection (PDA) and LC-MS/MS analysis. A sensitive and reliable RP-HPLC method with fluorescence detection was developed and validated for the simultaneous analysis of MCPT and HCPT in rat plasma. This method was also applied to the pharmacokinetic study of MCPT and its metabolite HCPT in rat plasma after intravenous administration.
In this study, the mean plasma concentration-time curves of MCPT and its metabolite HCPT were determined for six rats each receiving a single5mg/kg i.v. dose of MCPT via the tail vein. After i.v. administration, the level of MCPT reached the maximum concentration, and declined immediately. HCPT concentration reached the maximum within the first5-10min post-administration of the dose, and after that HCPT level declined promptly.. The ratio of AUC0-∞of HCPT to that of MCPT was about150%, which demonstrated that the metabolism to the demethylated HCPT was the dominant metabolic reaction for MCPT in rats.
The tissue distribution of MCPT and its metabolite HCPT were determined for rats after each receiving a single5mg/kg i.v. dose of MCPT via the tail vein. These results indicated that the content of MCPT was higher in liver, spleen and kidney, and was lowest in brain, while the content of HCPT was higher in liver and kidney than in other tissues.
At last, the accumulation of MCPT and and its metabolite HCPT in excretion pathway was investigated after receiving a single5mg/kg i.v. dose of MCPT via the tail vein. The results indicated that MCPT was excreted in bile mostly, while HCPT was mainly excreted in feces.
In summary, a pharmacokinetic study of MCPT and and its metabolite HCPT in rats were investigated, and the absorption, distribution, metabolism, excretion of MCPT was clarified, in order to provide a theories basis for the clinical medication, reasonable development and application of MCPT.
引文
[1]Wall ME, Wani MC, Cook CE, Palmer KH, McPhail AT, Sim GA. Plant Antitumor Agents. I. The Isolation and Structure of Camptothecin, a Novel Alkaloidal Leukemia and Tumor Inhibitor from Camptotheca acuminata. J Am Chem Soc.1966,88:3888-90.
[2]Shamma M, St Georgiev V. Camptothecin. J Pharm Sci.1974,63:163-83.
[3]Gottlieb JA, Guarino AM, Call JB, Oliverio VT, Block JB. Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC-100880). Cancer Chemother Rep.1970,54:461-70.
[4]Schultz AG. Camptothecin. Chem Rev.1973,73:385-405.
[5]Moertel CG, Schutt AJ, Reitemeier RJ, Hahn RG. Phase II study of camptothecin (NSC-100880) in the treatment of advanced gastrointestinal cancer. Cancer Chemother Rep.1972,56:95-101.
[6]Hsiang YH, Hertzberg R, Hecht S, Liu LF. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase Ⅰ. J Biol Chem.1985, 260:14873-8.
[7]DeWys WD, Humphreys SR, Goldin A. Studies on therapeutic effectiveness of drugs with tumor weight and survival time indices of Walker 256 carcinosarcoma. Cancer Chemother Rep.1968,52:229-42.
[8]Spataro A, Kessel D. Studies on camptothecin-induced degradation and apparent reaggregation of DNA from L1210 cells. Biochem Biophys Res Commun.1972,48:643-8.
[9]Kessel D, Bosmann HB, Lohr K. Camptothecin effects on DNA synthesis in murine leukemia cells. Biochim Biophys Acta.1972,269:210-6.
[10]李春杰,谷莹,韩应许,周凯.喜树碱及其衍生物的研究进展.中国药物化学杂志.2003,13：306-10.
[11]Pizzolato JF, Saltz LB. The camptothecins. Lancet.2003,361:2235-42.
[12]郭宏红.羟基喜树碱微胶囊药代动力学研究.东北林业大学硕士论文.2011.
[13]Pommier Y. Topoisomerase I inhibitors:camptothecins and beyond. Nat Rev Cancer.2006,6:789-802.
[14]Nitiss J, Wang JC. DNA topoisomerase-targeting antitumor drugs can be studied in yeast. Proc Natl Acad Sci U S A.1988,85:7501-5.
[15]Pommier Y, Pourquier P, Urasaki Y, Wu J, Laco GS. Topoisomerase I inhibitors:selectivity and cellular resistance. Drug Resist Updat.1999,2:307-18.
[16]Hautefaye P, Cimetiere B, Pierre A, Leonce S, Hickman J, Laine W, et al. Synthesis and pharmacological evaluation of novel non-lactone analogues of camptothecin. Bioorg Med Chem Lett.2003,13:2731-5.
[17]李思阳.羟基喜树碱缓释制剂的制备及其表征.东北林业大学硕士论文.2012.
[18]Wall ME, Wani MC. Camptothecin. Discovery to clinic. Ann N Y Acad Sci. 1996,803:1-12.
[19]蔡俊超,殷孟光,闵爱珠,冯大为,张薛鑫.dl-10-羟基喜树碱及d1-10-甲氧基喜树碱的全合成.化学学报.1981,2：171-6.
[20]Wani MC, Ronman PE, Lindley JT, Wall ME. Plant antitumor agents.18. Synthesis and biological activity of camptothecin analogues. J Med Chem.1980, 23:554-60.
[21]Wani MC, Wall ME. Plant Antitumor Agents.Ⅱ. The Structure of Two New Alkaloids from Camptotheca acuminata The Journal of Organic Chemistry. 1969,34:1364-7.
[22]Tafur S, Nelson JD, DeLong DC, Svoboda GH. Antiviral components of Ophiorrhiza mungos. Isolation of camptothecin and 10-methoxycamptothecin. Lloydia.1976,39:261-2.
[23]Horwitz SB, Chang CK, Grollman AP. Studies on camptothecin. Ⅰ. Effects of nucleic acid and protein synthesis. Mol Pharmacol.1971,7:632-44.
[24]徐任生,赵志远,林隆泽,脊传凤.抗瘤植物喜树化学成分的研究II.喜树果中的化学成分.化学学报.1977,35：193-200.
[25]Lin L, Zhao Z, Xu R. Chemical constituents of the anticancer plant Camototheca acuminata Dence Ⅰ. chemical constituents of the roots of Camototheca acuminata Dence. Acta Chimica Sinica.1977,35:227-31.
[26]秦庆亮,常用,李安琪.羟基喜树碱促进胃癌细胞凋亡的临床研究.中国肿瘤临床.1999,26：696-9.
[27]董生,肖湘生,郝楠馨.羟基喜树碱微球肝动脉化疗栓塞治疗原发性肝癌.中国医学计算机成像杂志.1999,5：55-8.
[28]张金声,路琦,姚雅玲.羟基喜树碱治疗慢性粒细胞白血病疗效分析.中国实验血液学杂志.2000,8：155-7.
[29]程鸣鸣,陈宗福,李红.羟基喜树碱灌注预防膀胧癌术后复发(附86例报告.临床泌尿外科杂志.2000,15：62-3.
[30]Grochow LB, Rowinsky EK, Johnson R, Ludeman S, Kaufmann SH, McCabe FL, et al. Pharmacokinetics and pharmacodynamics of topotecan in patients with advanced cancer. Drug Metab Dispos.1992,20:706-13.
[31]董婧,郭盛磊,王洋.新型药物传递系统与喜树碱功能的发挥.中国组织工程研究与临床康复.2008,12：4507-10.
[32]周卫,丁逸梅,王丽杰.脂质体对羟基喜树碱内酯环的保护.中国药学杂志.2005,40：688-90.
[33]何文,吴燕,代文兵,陈建.羟基喜树碱包衣纳米脂质体的制备及在小鼠体内组织分布的研究.中国药学杂志.2006,41：196-200.
[34]沈洁,王青松,许向阳,周建平.喜树碱类衍生物脂质体的研究进展.中国药科大学学报.2007,38：380-4.
[35]Opanasopit P, Yokoyama M, Watanabe M, Kawano K, Maitani Y, Okano T. Influence of serum and albumins from different species on stability of camptothecin-loaded micelles. J Control Release.2005,104:313-21.
[36]Yang L, Cui F, Cun D, Tao A, Shi K, Lin W. Preparation, characterization and biodistribution of the lactone form of 10-hydroxycamptothecin (HCPT)-loaded bovine serum albumin (BSA) nanoparticles. Int J Pharm.2007,340:163-72.
[37]Zhang L, Yang M, Wang Q, Li Y, Guo R, Jiang X, et al.10-Hydroxycamptothecin loaded nanoparticles:preparation and antitumor activity in mice. J Control Release.2007,119:153-62.
[38]梁振鹏,王朝阳,孙启龙,童真.LbL层层纳米自组装法制备新型微胶囊.化学进展.2004,16：485-91.
[39]Guo S, Zheng J, Dong J, Guo N, Jing L, Yue X, et al. Iron/dextran sulfate multilayered microcapsules for controlled release of 10-hydroxycamptothecin. Int J Biol Macromol.2011,49:409-15.
[40]李思阳,郑健,骆沙曼,王洋.10-羟基喜树碱的聚赖氨酸／海藻酸钠微胶囊的制备及其体外释药特性研究.中草药.2011,49：1724-7.
[41]龚明涛,张钧寿,沈益.羟基喜树碱纳米乳的制备及其抗癌作用初步研究.中国天然药物.2005,3：41-3.
[42]王广基,刘晓东,柳晓泉.药物代谢动力学.北京：化学工业出版社.2005.
[43]金有豫.药理学(第五版).人民卫生出版社.2001.
[44]吴钟琪,周宏灏,许树梧.全科医学临床药物学.科学出版社.2001.
[45]戴得哉.临床药理学.中国医药科技出版社.2002.
[46]郭娜.红景天苷及其代谢产物酪醇在大鼠体内的药物代谢动力学研究.东北林业大学博士论文.2012.
[47]D'Esposito F, Tattam BN, Ramzan I, Murray M. A liquid chromatography/electrospray ionization mass spectrometry (LC-MS/MS) assay for the determination of irinotecan (CPT-11) and its two major metabolites in human liver microsomal incubations and human plasma samples. J Chromatogr B Analyt Technol Biomed Life Sci.2008,875:522-30.
[48]Mathijssen RH, van Alphen RJ, Verweij J, Loos WJ, Nooter K, Stoter G, et al. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res.2001,7:2182-94.
[49]谭慧心.拓扑异构酶I抑制剂研究进展.中国药理学通报.2009,25：436-41.
[50]Zucker D, Barenholz Y. Optimization of vincristine-topotecan combination--paving the way for improved chemotherapy regimens by nanoliposomes. J Control Release.2010,146:326-33.
[51]Tomkinson B, Bendele R, Giles FJ, Brown E, Gray A, Hart K, et al. OSI-211, a novel liposomal topoisomerase I inhibitor, is active in SCID mouse models of human AML and ALL. Leuk Res.2003,27:1039-50.
[52]张力,李苏,廖海,姜文奇,管忠震.羟基喜树碱I期药代动力学及人体耐受性临床研究.癌症.2001,20：1391-5.
[53]潘宏.羟喜树碱国内临床应用现状.中国药师.2009,12：967-9.
[54]阎昭,赵国臣,焦建杰.注射用纳米羟喜树碱与注射用羟喜树碱在小鼠体内的组织分布比较.中国新药与临床杂志.2005,24：108-12.
[55]Dancey J, Eisenhauer EA. Current perspectives on camptothecins in cancer treatment. Br J Cancer.1996,74:327-38.
[56]Hinz HR, Harris NJ, Natelson EA, Giovanella BC. Pharmacokinetics of the in vivo and in vitro conversion of 9-nitro-20(S)-camptothecin to 9-amino-20(S)-camptothecin in humans, dogs, and mice. Cancer Res.1994,54:3096-100.
[57]Takimoto CH, Thomas R. The clinical development of 9-aminocamptothecin. Ann N Y Acad Sci.2000,922:224-36.
[58]Zhong DF, Li K, Xu JH, Du Y, Zhang YF. Pharmacokinetics of 9-nitro-20(S)-camptothecin in rats. Acta Pharmacol Sin.2003,24:256-62.
[59]Lavergne O, Lesueur-Ginot L, Rodas FP, Bigg DCH. BN 80245:an E-ring modified camptothecin with potent antiproliferative and topoisomerase I inhibitory activities. Bioorganic & Medicinal Chemistry Letters.1997,7:2235-8.
[60]Gelderblom H, Salazar R, Verweij J, Pentheroudakis G, de Jonge MJ, Devlin M, et al. Phase I pharmacological and bioavailability study of oral diflomotecan (BN80915), a novel E-ring-modified camptothecin analogue in adults with solid tumors. Clin Cancer Res.2003,9:4101-7.
[61]Kroep JR, Gelderblom H. Diflomotecan, a promising homocamptothecin for cancer therapy. Expert Opin Investig Drugs.2009,18:69-75.
[62]Scott L, Soepenberg O, Verweij J, de Jonge MJ, Th Planting AS, McGovern D, et al. A multicentre phase I and pharmacokinetic study of BN80915 (diflomotecan) administered daily as a 20-min intravenous infusion for 5 days every 3 weeks to patients with advanced solid tumours. Ann Oncol.2007,18: 569-75.
[63]李磊,杨雨晗,王双,王曼晋,李好,刘小飞.细胞活性检测方法之比较.生物学杂志.2011,28：87-93.
[64]Zhang ZW, Patchett SE, Farthing MJ. Topoisomerase I inhibitor (camptothecin)-induced apoptosis in human gastric cancer cells and the role of wild-type p53 in the enhancement of its cytotoxicity. Anticancer Drugs.2000,11: 757-64.
[65]Moody TW, Fuselier J, Coy DH, Mantey S, Pradhan T, Nakagawa T, et al. Camptothecin-somatostatin conjugates inhibit the growth of small cell lung cancer cells. Peptides.2005,26:1560-6.
[66]Banasiak D, Barnetson AR, Odell RA, Mameghan H, Russell PJ. Comparison between the clonogenic, MTT, and SRB assays for determining radiosensitivity in a panel of human bladder cancer cell lines and a ureteral cell line. Radiat Oncol Investig.1999,7:77-85.
[67]Yao L, Zhao X, Li Q, Zu Y, Fu Y, Zu B, et al. In vitro and in vivo evaluation of camptothecin nanosuspension:a novel formulation with high antitumor efficacy and low toxicity. Int J Pharm.2012,423:586-8.
[68]Li Q, Qiu W, Zhu Q, Zu Y, Deng X, Zhao T, et al. Camptothecin-20(s)-O-[N-(3'alpha,12'alpha-dihydroxy-24'-carbonyl-5'beta-cholan)]-lysine, a novel camptothecin analogue, induces apoptosis towards hepatocellular carcinoma SMMC-7721 cells. Molecules.2011,16:7803-14.
[69]栾家杰,宋建国.药物转运体与药物体内过程.安徽医药.2005,9：721-3.
[70]沈琦,胡海红,曾苏.转运体稳定表达的验证方法及其研究进展.中国现代应用药学.2012,29：603-9.
[71]Roth M, Obaidat A, Hagenbuch B. OATPs, OATs and OCTs:the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br J Pharmacol.2012,165:1260-87.
[72]刘涛,刘克辛.药物转运体的变化对肝脏疾病的影响.中华临床医师杂志(电子版).2011,5：2982-5.
[73]宋必卫,周彦君.有机阴离子转运蛋白的研究进展.生理科学进展. 2012,43：11-6.
[74]李洁,王艳娇,孙进,何仲贵.转运蛋白在药物肾脏转运中的重要作用.中国临床药理学杂志.2006,22：303-6.
[75]Ho ES, Lin DC, Mendel DB, Cihlar T. Cytotoxicity of antiviral nucleotides adefovir and cidofovir is induced by the expression of human renal organic anion transporter 1. J Am Soc Nephrol.2000,11:383-93.
[76]Jariyawat S, Sekine T, Takeda M, Apiwattanakul N, Kanai Y, Sophasan S, et al. The interaction and transport of beta-lactam antibiotics with the cloned rat renal organic anion transporter 1. J Pharmacol Exp Ther.1999,290:672-7.
[77]吕森森,李长贵.有机阴离子转运蛋白1和3的研究进展.齐鲁医学杂志.2009,24：371-2.
[78]Cutler MJ, Choo EF. Overview of SLC22A and SLCO families of drug uptake transporters in the context of cancer treatments. Curr Drug Metab.2011, 12:793-807.
[79]Ahn SY, Nigam SK. Toward a systems level understanding of organic anion and other multispecific drug transporters:a remote sensing and signaling hypothesis. Mol Pharmacol.2009,76:481-90.
[80]Islam R, Anzai N, Ahmed N, Ellapan B, Jin CJ, Srivastava S, et al. Mouse organic anion transporter 2 (mOat2) mediates the transport of short chain fatty acid propionate. J Pharmacol Sci.2008,106:525-8.
[81]杨聪,刘云祥,陈文生.人有机阴离子OATPs在药物分布中的作用研究进展.西南国防医药.2010,20：672-4.
[82]Meier-Abt F, Mokrab Y, Mizuguchi K. Organic anion transporting polypeptides of the OATP/SLCO superfamily:identification of new members in nonmammalian species, comparative modeling and a potential transport mode. J Membr Biol.2005,208:213-27.
[83]彭丹,夏春华,熊玉抑.有机阴离子转运多肤1A2对药物转运的影响.中国临床药理学与治疗学.2010,15：464-9.
[84]张伟,贺毅憬,周宏灏.有机阴离子转运多肽1B1的遗传药理学进展.中国药理学与治疗学.2008,13：721-9.
[85]Smith NF, Figg WD, Sparreboom A. Role of the liver-specific transporters OATP1B1 and OATP1B3 in governing drug elimination. Expert Opin Drug Metab Toxicol.2005,1:429-45.
[86]李雪,李燕.有机阴离子转运多肽1B3的研究进展.药学学报.2011,46：1279-85.
[87]Hsiang B, Zhu Y, Wang Z, Wu Y, Sasseville V, Yang WP, et al. A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem.1999,274:37161-8.
[88]温爱萍,徐小薇.有机阴离子转运多肽1B1的研究进展.中国药学杂志.2008,43：1765-9.
[89]Tirona RG, Leake BF, Merino G, Kim RB. Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem.2001,276:35669-75.
[90]Nozawa T, Nakajima M, Tamai I, Noda K, Nezu J, Sai Y, et al. Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9):allele frequencies in the Japanese population and functional analysis. J Pharmacol Exp Ther.2002,302:804-13.
[91]Konig J, Cui Y, Nies AT, Keppler D. A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am J Physiol Gastrointest Liver Physiol.2000,278:G156-64.
[92]Xiang X, Jada SR, Li HH, Fan L, Tham LS, Wong CI, et al. Pharmacogenetics of SLCO1B1 gene and the impact of *1b and *15 haplotypes on irinotecan disposition in Asian cancer patients. Pharmacogenet Genomics. 2006,16:683-91.
[93]Wright JL, Kwon EM, Ostrander EA, Montgomery RB, Lin DW, Vessella R, et al. Expression of SLCO transport genes in castration-resistant prostate cancer and impact of genetic variation in SLCO1B3 and SLCO2B1 on prostate cancer outcomes. Cancer Epidemiol Biomarkers Prev.2011,20:619-27.
[94]Sissung TM, Baum CE, Kirkland CT, Gao R, Gardner ER, Figg WD. Pharmacogenetics of membrane transporters:an update on current approaches. Mol Biotechnol.2010,44:152-67.
[95]黄九九,李楠,余业进,洪梅.有机阴离子转运多肽及其对药物吸收、分布和排出的影响.今日药学.2010,20：1-4.
[96]Kobayashi D, Nozawa T, Imai K, Nezu J, Tsuji A, Tamai I. Involvement of human organic anion transporting polypeptide OATP-B (SLC21A9) in pH-dependent transport across intestinal apical membrane. J Pharmacol Exp Ther. 2003,306:703-8.
[97]Seki S, Kobayashi M, Itagaki S, Hirano T, Iseki K. Contribution of organic anion transporting polypeptide OATP2B1 to amiodarone accumulation in lung epithelial cells. Biochim Biophys Acta.2009,1788:911-7.
[98]韩林志,周宏灏.有机阳离子转运体的基因多态性研究进展.中国临床药理学与治疗学.2009,14：460-5.
[99]高纯颖,陈笑艳,钟大放.转运体在药物经肝脏清除过程中的作用.药学学报.2012,47：565-72.
[100]Gupta S, Wulf G, Henjakovic M, Koepsell H, Burckhardt G, Hagos Y. Human organic cation transporter 1 is expressed in lymphoma cells and increases susceptibility to irinotecan and paclitaxel. J Pharmacol Exp Ther.2012,341:16-23.
[101]卢战军,郑萍.肉毒碱/有机阳离子转运体基因多态性与克罗恩病相关性的研究进展.胃肠病学.2008,13：61-5.
[102]Li M, Jin W, Jiang C, Zheng C, Tang W, You T, et al.7-Cycloalkylcamptothecin derivatives:Preparation and biological evaluation. Bioorg Med Chem Lett.2009,19:4107-9.
[103]Vladu B, Woynarowski JM, Manikumar G, Wani MC, Wall ME, Von Hoff DD, et al.7- and 10-substituted camptothecins:dependence of topoisomerase I-DNA cleavable complex formation and stability on the 7- and 10-substituents. Mol Pharmacol.2000,57:243-51.
[104]Zhou F, Zhu L, Cui PH, Church WB, Murray M. Functional characterization of nonsynonymous single nucleotide polymorphisms in the human organic anion transporter 4 (hOAT4). Br J Pharmacol.2010,159:419-27.
[105]Cheng Y, Prusoff WH. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (150) of an enzymatic reaction. Biochem Pharmacol.1973,22:3099-108.
[106]陈西敬,王广基.药物转运蛋白在药物吸收、分布和排泄中的作用及对新药研发的意义.中国药科大学学报.2003,36：483-6.
[107]Sweet DH. Organic anion transporter (Slc22a) family members as mediators of toxicity. Toxicol Appl Pharmacol.2005,204:198-215.
[108]Ueo H, Motohashi H, Katsura T, Inui K. Human organic anion transporter hOAT3 is a potent transporter of cephalosporin antibiotics, in comparison with hOAT1. Biochem Pharmacol.2005,70:1104-13.
[109]Fernandez P, Morales L, Vazquez C, Bermejo AM, Tabernero MJ. HPLC-DAD determination of opioids, cocaine and their metabolites in plasma. Forensic Sci Int.2006,161:31-5.
[110]Chen J, Lin H, Hu M. Metabolism of flavonoids via enteric recycling:role of intestinal disposition. J Pharmacol Exp Ther.2003,304:1228-35.
[111]Poujol S, Pinguet F, Malosse F, Astre C, Ychou M, Culine S, et al. Sensitive HPLC-fluorescence method for irinotecan and four major metabolites in human plasma and saliva:application to pharmacokinetic studies. Clin Chem.2003,49: 1900-8.
[112]Hu ZP, Yang XX, Chen X, Chan E, Duan W, Zhou SF. Simultaneous determination of irinotecan (CPT-11) and SN-38 in tissue culture media and cancer cells by high performance liquid chromatography:application to cellular metabolism and accumulation studies. J Chromatogr B Analyt Technol Biomed Life Sci.2007,850:575-80.
[113]Ragot S, Marquet P, Lachatre F, Rousseau A, Lacassie E, Gaulier JM, et al. Sensitive determination of irinotecan (CPT-11) and its active metabolite SN-38 in human serum using liquid chromatography-electrospray mass spectrometry. J Chromatogr B Biomed Sci Appl.1999,736:175-84.
[114]Guo S, Zheng J, Dong J, Guo N, Jing L, Yue X, et al. Iron/dextran sulfate multilayered microcapsules for controlled release of 10-hydroxycamptothecin. Int J Biol Macromol.2011,49:409-15.
[115]Guo H, Zheng J, Jing L, Li S, Yan X, Wang Y. Determination of the plasma concentration of 10-hydroxycamptothecin in mice by RP-HPLC. China Phamacy. 2011,22:13-5.
[116]Liu X, Wang Y, Vardeman D, Cao Z, Giovanella B. Development and validation of a reverse-phase HPLC with fluorescence detector method for simultaneous determination of CZ48 and its active metabolite camptothecin in mouse plasma. J Chromatogr B Analyt Technol Biomed Life Sci.2008,867:84-9.
[117]Loh JP, Ahmed AE. Determination of camptothecin in biological fluids using reversed-phase high-performance liquid chromatography with fluorescence detection. J Chromatogr.1990,530:367-76.
[118]Platzer P, Thalhammer T, Reznicek G, Hamilton G, Zhang R, Jager W. Metabolism and biliary excretion of the novel anticancer agent 10-hydroxycamptothecin in the isolated perfused rat liver. Int J Oncol.2001,19: 1287-93.
[2]Shamma M, St Georgiev V. Camptothecin. J Pharm Sci.1974,63:163-83.
[3]Gottlieb JA, Guarino AM, Call JB, Oliverio VT, Block JB. Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC-100880). Cancer Chemother Rep.1970,54:461-70.
[4]Schultz AG. Camptothecin. Chem Rev.1973,73:385-405.
[5]Moertel CG, Schutt AJ, Reitemeier RJ, Hahn RG. Phase II study of camptothecin (NSC-100880) in the treatment of advanced gastrointestinal cancer. Cancer Chemother Rep.1972,56:95-101.
[6]Hsiang YH, Hertzberg R, Hecht S, Liu LF. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase Ⅰ. J Biol Chem.1985, 260:14873-8.
[7]DeWys WD, Humphreys SR, Goldin A. Studies on therapeutic effectiveness of drugs with tumor weight and survival time indices of Walker 256 carcinosarcoma. Cancer Chemother Rep.1968,52:229-42.
[8]Spataro A, Kessel D. Studies on camptothecin-induced degradation and apparent reaggregation of DNA from L1210 cells. Biochem Biophys Res Commun.1972,48:643-8.
[9]Kessel D, Bosmann HB, Lohr K. Camptothecin effects on DNA synthesis in murine leukemia cells. Biochim Biophys Acta.1972,269:210-6.
[10]李春杰,谷莹,韩应许,周凯.喜树碱及其衍生物的研究进展.中国药物化学杂志.2003,13：306-10.
[11]Pizzolato JF, Saltz LB. The camptothecins. Lancet.2003,361:2235-42.
[12]郭宏红.羟基喜树碱微胶囊药代动力学研究.东北林业大学硕士论文.2011.
[13]Pommier Y. Topoisomerase I inhibitors:camptothecins and beyond. Nat Rev Cancer.2006,6:789-802.
[14]Nitiss J, Wang JC. DNA topoisomerase-targeting antitumor drugs can be studied in yeast. Proc Natl Acad Sci U S A.1988,85:7501-5.
[15]Pommier Y, Pourquier P, Urasaki Y, Wu J, Laco GS. Topoisomerase I inhibitors:selectivity and cellular resistance. Drug Resist Updat.1999,2:307-18.
[16]Hautefaye P, Cimetiere B, Pierre A, Leonce S, Hickman J, Laine W, et al. Synthesis and pharmacological evaluation of novel non-lactone analogues of camptothecin. Bioorg Med Chem Lett.2003,13:2731-5.
[17]李思阳.羟基喜树碱缓释制剂的制备及其表征.东北林业大学硕士论文.2012.
[18]Wall ME, Wani MC. Camptothecin. Discovery to clinic. Ann N Y Acad Sci. 1996,803:1-12.
[19]蔡俊超,殷孟光,闵爱珠,冯大为,张薛鑫.dl-10-羟基喜树碱及d1-10-甲氧基喜树碱的全合成.化学学报.1981,2：171-6.
[20]Wani MC, Ronman PE, Lindley JT, Wall ME. Plant antitumor agents.18. Synthesis and biological activity of camptothecin analogues. J Med Chem.1980, 23:554-60.
[21]Wani MC, Wall ME. Plant Antitumor Agents.Ⅱ. The Structure of Two New Alkaloids from Camptotheca acuminata The Journal of Organic Chemistry. 1969,34:1364-7.
[22]Tafur S, Nelson JD, DeLong DC, Svoboda GH. Antiviral components of Ophiorrhiza mungos. Isolation of camptothecin and 10-methoxycamptothecin. Lloydia.1976,39:261-2.
[23]Horwitz SB, Chang CK, Grollman AP. Studies on camptothecin. Ⅰ. Effects of nucleic acid and protein synthesis. Mol Pharmacol.1971,7:632-44.
[24]徐任生,赵志远,林隆泽,脊传凤.抗瘤植物喜树化学成分的研究II.喜树果中的化学成分.化学学报.1977,35：193-200.
[25]Lin L, Zhao Z, Xu R. Chemical constituents of the anticancer plant Camototheca acuminata Dence Ⅰ. chemical constituents of the roots of Camototheca acuminata Dence. Acta Chimica Sinica.1977,35:227-31.
[26]秦庆亮,常用,李安琪.羟基喜树碱促进胃癌细胞凋亡的临床研究.中国肿瘤临床.1999,26：696-9.
[27]董生,肖湘生,郝楠馨.羟基喜树碱微球肝动脉化疗栓塞治疗原发性肝癌.中国医学计算机成像杂志.1999,5：55-8.
[28]张金声,路琦,姚雅玲.羟基喜树碱治疗慢性粒细胞白血病疗效分析.中国实验血液学杂志.2000,8：155-7.
[29]程鸣鸣,陈宗福,李红.羟基喜树碱灌注预防膀胧癌术后复发(附86例报告.临床泌尿外科杂志.2000,15：62-3.
[30]Grochow LB, Rowinsky EK, Johnson R, Ludeman S, Kaufmann SH, McCabe FL, et al. Pharmacokinetics and pharmacodynamics of topotecan in patients with advanced cancer. Drug Metab Dispos.1992,20:706-13.
[31]董婧,郭盛磊,王洋.新型药物传递系统与喜树碱功能的发挥.中国组织工程研究与临床康复.2008,12：4507-10.
[32]周卫,丁逸梅,王丽杰.脂质体对羟基喜树碱内酯环的保护.中国药学杂志.2005,40：688-90.
[33]何文,吴燕,代文兵,陈建.羟基喜树碱包衣纳米脂质体的制备及在小鼠体内组织分布的研究.中国药学杂志.2006,41：196-200.
[34]沈洁,王青松,许向阳,周建平.喜树碱类衍生物脂质体的研究进展.中国药科大学学报.2007,38：380-4.
[35]Opanasopit P, Yokoyama M, Watanabe M, Kawano K, Maitani Y, Okano T. Influence of serum and albumins from different species on stability of camptothecin-loaded micelles. J Control Release.2005,104:313-21.
[36]Yang L, Cui F, Cun D, Tao A, Shi K, Lin W. Preparation, characterization and biodistribution of the lactone form of 10-hydroxycamptothecin (HCPT)-loaded bovine serum albumin (BSA) nanoparticles. Int J Pharm.2007,340:163-72.
[37]Zhang L, Yang M, Wang Q, Li Y, Guo R, Jiang X, et al.10-Hydroxycamptothecin loaded nanoparticles:preparation and antitumor activity in mice. J Control Release.2007,119:153-62.
[38]梁振鹏,王朝阳,孙启龙,童真.LbL层层纳米自组装法制备新型微胶囊.化学进展.2004,16：485-91.
[39]Guo S, Zheng J, Dong J, Guo N, Jing L, Yue X, et al. Iron/dextran sulfate multilayered microcapsules for controlled release of 10-hydroxycamptothecin. Int J Biol Macromol.2011,49:409-15.
[40]李思阳,郑健,骆沙曼,王洋.10-羟基喜树碱的聚赖氨酸／海藻酸钠微胶囊的制备及其体外释药特性研究.中草药.2011,49：1724-7.
[41]龚明涛,张钧寿,沈益.羟基喜树碱纳米乳的制备及其抗癌作用初步研究.中国天然药物.2005,3：41-3.
[42]王广基,刘晓东,柳晓泉.药物代谢动力学.北京：化学工业出版社.2005.
[43]金有豫.药理学(第五版).人民卫生出版社.2001.
[44]吴钟琪,周宏灏,许树梧.全科医学临床药物学.科学出版社.2001.
[45]戴得哉.临床药理学.中国医药科技出版社.2002.
[46]郭娜.红景天苷及其代谢产物酪醇在大鼠体内的药物代谢动力学研究.东北林业大学博士论文.2012.
[47]D'Esposito F, Tattam BN, Ramzan I, Murray M. A liquid chromatography/electrospray ionization mass spectrometry (LC-MS/MS) assay for the determination of irinotecan (CPT-11) and its two major metabolites in human liver microsomal incubations and human plasma samples. J Chromatogr B Analyt Technol Biomed Life Sci.2008,875:522-30.
[48]Mathijssen RH, van Alphen RJ, Verweij J, Loos WJ, Nooter K, Stoter G, et al. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res.2001,7:2182-94.
[49]谭慧心.拓扑异构酶I抑制剂研究进展.中国药理学通报.2009,25：436-41.
[50]Zucker D, Barenholz Y. Optimization of vincristine-topotecan combination--paving the way for improved chemotherapy regimens by nanoliposomes. J Control Release.2010,146:326-33.
[51]Tomkinson B, Bendele R, Giles FJ, Brown E, Gray A, Hart K, et al. OSI-211, a novel liposomal topoisomerase I inhibitor, is active in SCID mouse models of human AML and ALL. Leuk Res.2003,27:1039-50.
[52]张力,李苏,廖海,姜文奇,管忠震.羟基喜树碱I期药代动力学及人体耐受性临床研究.癌症.2001,20：1391-5.
[53]潘宏.羟喜树碱国内临床应用现状.中国药师.2009,12：967-9.
[54]阎昭,赵国臣,焦建杰.注射用纳米羟喜树碱与注射用羟喜树碱在小鼠体内的组织分布比较.中国新药与临床杂志.2005,24：108-12.
[55]Dancey J, Eisenhauer EA. Current perspectives on camptothecins in cancer treatment. Br J Cancer.1996,74:327-38.
[56]Hinz HR, Harris NJ, Natelson EA, Giovanella BC. Pharmacokinetics of the in vivo and in vitro conversion of 9-nitro-20(S)-camptothecin to 9-amino-20(S)-camptothecin in humans, dogs, and mice. Cancer Res.1994,54:3096-100.
[57]Takimoto CH, Thomas R. The clinical development of 9-aminocamptothecin. Ann N Y Acad Sci.2000,922:224-36.
[58]Zhong DF, Li K, Xu JH, Du Y, Zhang YF. Pharmacokinetics of 9-nitro-20(S)-camptothecin in rats. Acta Pharmacol Sin.2003,24:256-62.
[59]Lavergne O, Lesueur-Ginot L, Rodas FP, Bigg DCH. BN 80245:an E-ring modified camptothecin with potent antiproliferative and topoisomerase I inhibitory activities. Bioorganic & Medicinal Chemistry Letters.1997,7:2235-8.
[60]Gelderblom H, Salazar R, Verweij J, Pentheroudakis G, de Jonge MJ, Devlin M, et al. Phase I pharmacological and bioavailability study of oral diflomotecan (BN80915), a novel E-ring-modified camptothecin analogue in adults with solid tumors. Clin Cancer Res.2003,9:4101-7.
[61]Kroep JR, Gelderblom H. Diflomotecan, a promising homocamptothecin for cancer therapy. Expert Opin Investig Drugs.2009,18:69-75.
[62]Scott L, Soepenberg O, Verweij J, de Jonge MJ, Th Planting AS, McGovern D, et al. A multicentre phase I and pharmacokinetic study of BN80915 (diflomotecan) administered daily as a 20-min intravenous infusion for 5 days every 3 weeks to patients with advanced solid tumours. Ann Oncol.2007,18: 569-75.
[63]李磊,杨雨晗,王双,王曼晋,李好,刘小飞.细胞活性检测方法之比较.生物学杂志.2011,28：87-93.
[64]Zhang ZW, Patchett SE, Farthing MJ. Topoisomerase I inhibitor (camptothecin)-induced apoptosis in human gastric cancer cells and the role of wild-type p53 in the enhancement of its cytotoxicity. Anticancer Drugs.2000,11: 757-64.
[65]Moody TW, Fuselier J, Coy DH, Mantey S, Pradhan T, Nakagawa T, et al. Camptothecin-somatostatin conjugates inhibit the growth of small cell lung cancer cells. Peptides.2005,26:1560-6.
[66]Banasiak D, Barnetson AR, Odell RA, Mameghan H, Russell PJ. Comparison between the clonogenic, MTT, and SRB assays for determining radiosensitivity in a panel of human bladder cancer cell lines and a ureteral cell line. Radiat Oncol Investig.1999,7:77-85.
[67]Yao L, Zhao X, Li Q, Zu Y, Fu Y, Zu B, et al. In vitro and in vivo evaluation of camptothecin nanosuspension:a novel formulation with high antitumor efficacy and low toxicity. Int J Pharm.2012,423:586-8.
[68]Li Q, Qiu W, Zhu Q, Zu Y, Deng X, Zhao T, et al. Camptothecin-20(s)-O-[N-(3'alpha,12'alpha-dihydroxy-24'-carbonyl-5'beta-cholan)]-lysine, a novel camptothecin analogue, induces apoptosis towards hepatocellular carcinoma SMMC-7721 cells. Molecules.2011,16:7803-14.
[69]栾家杰,宋建国.药物转运体与药物体内过程.安徽医药.2005,9：721-3.
[70]沈琦,胡海红,曾苏.转运体稳定表达的验证方法及其研究进展.中国现代应用药学.2012,29：603-9.
[71]Roth M, Obaidat A, Hagenbuch B. OATPs, OATs and OCTs:the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br J Pharmacol.2012,165:1260-87.
[72]刘涛,刘克辛.药物转运体的变化对肝脏疾病的影响.中华临床医师杂志(电子版).2011,5：2982-5.
[73]宋必卫,周彦君.有机阴离子转运蛋白的研究进展.生理科学进展. 2012,43：11-6.
[74]李洁,王艳娇,孙进,何仲贵.转运蛋白在药物肾脏转运中的重要作用.中国临床药理学杂志.2006,22：303-6.
[75]Ho ES, Lin DC, Mendel DB, Cihlar T. Cytotoxicity of antiviral nucleotides adefovir and cidofovir is induced by the expression of human renal organic anion transporter 1. J Am Soc Nephrol.2000,11:383-93.
[76]Jariyawat S, Sekine T, Takeda M, Apiwattanakul N, Kanai Y, Sophasan S, et al. The interaction and transport of beta-lactam antibiotics with the cloned rat renal organic anion transporter 1. J Pharmacol Exp Ther.1999,290:672-7.
[77]吕森森,李长贵.有机阴离子转运蛋白1和3的研究进展.齐鲁医学杂志.2009,24：371-2.
[78]Cutler MJ, Choo EF. Overview of SLC22A and SLCO families of drug uptake transporters in the context of cancer treatments. Curr Drug Metab.2011, 12:793-807.
[79]Ahn SY, Nigam SK. Toward a systems level understanding of organic anion and other multispecific drug transporters:a remote sensing and signaling hypothesis. Mol Pharmacol.2009,76:481-90.
[80]Islam R, Anzai N, Ahmed N, Ellapan B, Jin CJ, Srivastava S, et al. Mouse organic anion transporter 2 (mOat2) mediates the transport of short chain fatty acid propionate. J Pharmacol Sci.2008,106:525-8.
[81]杨聪,刘云祥,陈文生.人有机阴离子OATPs在药物分布中的作用研究进展.西南国防医药.2010,20：672-4.
[82]Meier-Abt F, Mokrab Y, Mizuguchi K. Organic anion transporting polypeptides of the OATP/SLCO superfamily:identification of new members in nonmammalian species, comparative modeling and a potential transport mode. J Membr Biol.2005,208:213-27.
[83]彭丹,夏春华,熊玉抑.有机阴离子转运多肤1A2对药物转运的影响.中国临床药理学与治疗学.2010,15：464-9.
[84]张伟,贺毅憬,周宏灏.有机阴离子转运多肽1B1的遗传药理学进展.中国药理学与治疗学.2008,13：721-9.
[85]Smith NF, Figg WD, Sparreboom A. Role of the liver-specific transporters OATP1B1 and OATP1B3 in governing drug elimination. Expert Opin Drug Metab Toxicol.2005,1:429-45.
[86]李雪,李燕.有机阴离子转运多肽1B3的研究进展.药学学报.2011,46：1279-85.
[87]Hsiang B, Zhu Y, Wang Z, Wu Y, Sasseville V, Yang WP, et al. A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem.1999,274:37161-8.
[88]温爱萍,徐小薇.有机阴离子转运多肽1B1的研究进展.中国药学杂志.2008,43：1765-9.
[89]Tirona RG, Leake BF, Merino G, Kim RB. Polymorphisms in OATP-C: identification of multiple allelic variants associated with altered transport activity among European- and African-Americans. J Biol Chem.2001,276:35669-75.
[90]Nozawa T, Nakajima M, Tamai I, Noda K, Nezu J, Sai Y, et al. Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9):allele frequencies in the Japanese population and functional analysis. J Pharmacol Exp Ther.2002,302:804-13.
[91]Konig J, Cui Y, Nies AT, Keppler D. A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am J Physiol Gastrointest Liver Physiol.2000,278:G156-64.
[92]Xiang X, Jada SR, Li HH, Fan L, Tham LS, Wong CI, et al. Pharmacogenetics of SLCO1B1 gene and the impact of *1b and *15 haplotypes on irinotecan disposition in Asian cancer patients. Pharmacogenet Genomics. 2006,16:683-91.
[93]Wright JL, Kwon EM, Ostrander EA, Montgomery RB, Lin DW, Vessella R, et al. Expression of SLCO transport genes in castration-resistant prostate cancer and impact of genetic variation in SLCO1B3 and SLCO2B1 on prostate cancer outcomes. Cancer Epidemiol Biomarkers Prev.2011,20:619-27.
[94]Sissung TM, Baum CE, Kirkland CT, Gao R, Gardner ER, Figg WD. Pharmacogenetics of membrane transporters:an update on current approaches. Mol Biotechnol.2010,44:152-67.
[95]黄九九,李楠,余业进,洪梅.有机阴离子转运多肽及其对药物吸收、分布和排出的影响.今日药学.2010,20：1-4.
[96]Kobayashi D, Nozawa T, Imai K, Nezu J, Tsuji A, Tamai I. Involvement of human organic anion transporting polypeptide OATP-B (SLC21A9) in pH-dependent transport across intestinal apical membrane. J Pharmacol Exp Ther. 2003,306:703-8.
[97]Seki S, Kobayashi M, Itagaki S, Hirano T, Iseki K. Contribution of organic anion transporting polypeptide OATP2B1 to amiodarone accumulation in lung epithelial cells. Biochim Biophys Acta.2009,1788:911-7.
[98]韩林志,周宏灏.有机阳离子转运体的基因多态性研究进展.中国临床药理学与治疗学.2009,14：460-5.
[99]高纯颖,陈笑艳,钟大放.转运体在药物经肝脏清除过程中的作用.药学学报.2012,47：565-72.
[100]Gupta S, Wulf G, Henjakovic M, Koepsell H, Burckhardt G, Hagos Y. Human organic cation transporter 1 is expressed in lymphoma cells and increases susceptibility to irinotecan and paclitaxel. J Pharmacol Exp Ther.2012,341:16-23.
[101]卢战军,郑萍.肉毒碱/有机阳离子转运体基因多态性与克罗恩病相关性的研究进展.胃肠病学.2008,13：61-5.
[102]Li M, Jin W, Jiang C, Zheng C, Tang W, You T, et al.7-Cycloalkylcamptothecin derivatives:Preparation and biological evaluation. Bioorg Med Chem Lett.2009,19:4107-9.
[103]Vladu B, Woynarowski JM, Manikumar G, Wani MC, Wall ME, Von Hoff DD, et al.7- and 10-substituted camptothecins:dependence of topoisomerase I-DNA cleavable complex formation and stability on the 7- and 10-substituents. Mol Pharmacol.2000,57:243-51.
[104]Zhou F, Zhu L, Cui PH, Church WB, Murray M. Functional characterization of nonsynonymous single nucleotide polymorphisms in the human organic anion transporter 4 (hOAT4). Br J Pharmacol.2010,159:419-27.
[105]Cheng Y, Prusoff WH. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (150) of an enzymatic reaction. Biochem Pharmacol.1973,22:3099-108.
[106]陈西敬,王广基.药物转运蛋白在药物吸收、分布和排泄中的作用及对新药研发的意义.中国药科大学学报.2003,36：483-6.
[107]Sweet DH. Organic anion transporter (Slc22a) family members as mediators of toxicity. Toxicol Appl Pharmacol.2005,204:198-215.
[108]Ueo H, Motohashi H, Katsura T, Inui K. Human organic anion transporter hOAT3 is a potent transporter of cephalosporin antibiotics, in comparison with hOAT1. Biochem Pharmacol.2005,70:1104-13.
[109]Fernandez P, Morales L, Vazquez C, Bermejo AM, Tabernero MJ. HPLC-DAD determination of opioids, cocaine and their metabolites in plasma. Forensic Sci Int.2006,161:31-5.
[110]Chen J, Lin H, Hu M. Metabolism of flavonoids via enteric recycling:role of intestinal disposition. J Pharmacol Exp Ther.2003,304:1228-35.
[111]Poujol S, Pinguet F, Malosse F, Astre C, Ychou M, Culine S, et al. Sensitive HPLC-fluorescence method for irinotecan and four major metabolites in human plasma and saliva:application to pharmacokinetic studies. Clin Chem.2003,49: 1900-8.
[112]Hu ZP, Yang XX, Chen X, Chan E, Duan W, Zhou SF. Simultaneous determination of irinotecan (CPT-11) and SN-38 in tissue culture media and cancer cells by high performance liquid chromatography:application to cellular metabolism and accumulation studies. J Chromatogr B Analyt Technol Biomed Life Sci.2007,850:575-80.
[113]Ragot S, Marquet P, Lachatre F, Rousseau A, Lacassie E, Gaulier JM, et al. Sensitive determination of irinotecan (CPT-11) and its active metabolite SN-38 in human serum using liquid chromatography-electrospray mass spectrometry. J Chromatogr B Biomed Sci Appl.1999,736:175-84.
[114]Guo S, Zheng J, Dong J, Guo N, Jing L, Yue X, et al. Iron/dextran sulfate multilayered microcapsules for controlled release of 10-hydroxycamptothecin. Int J Biol Macromol.2011,49:409-15.
[115]Guo H, Zheng J, Jing L, Li S, Yan X, Wang Y. Determination of the plasma concentration of 10-hydroxycamptothecin in mice by RP-HPLC. China Phamacy. 2011,22:13-5.
[116]Liu X, Wang Y, Vardeman D, Cao Z, Giovanella B. Development and validation of a reverse-phase HPLC with fluorescence detector method for simultaneous determination of CZ48 and its active metabolite camptothecin in mouse plasma. J Chromatogr B Analyt Technol Biomed Life Sci.2008,867:84-9.
[117]Loh JP, Ahmed AE. Determination of camptothecin in biological fluids using reversed-phase high-performance liquid chromatography with fluorescence detection. J Chromatogr.1990,530:367-76.
[118]Platzer P, Thalhammer T, Reznicek G, Hamilton G, Zhang R, Jager W. Metabolism and biliary excretion of the novel anticancer agent 10-hydroxycamptothecin in the isolated perfused rat liver. Int J Oncol.2001,19: 1287-93.