Pharmacokinetic Studies on Drug Excretion Mechanism Mediated by P-Glycoprotein
Pharmacokinetic Studies on Drug Excretion Mechanism Mediated by P-Glycoprotein
批准号:
06672233
负责人:
TANIGAWARA Yusuke
金额:
$1.41万
依托单位:
依托单位国家:
日本
项目类别:
Grant-in-Aid for General Scientific Research (C)
财政年份:
1994
资助国家:
日本
项目状态:
已结题
起止时间:
1994 至 1995
中文摘要
为了研究P-糖蛋白转运药物的机制,对其构效关系进行了定量研究。将人MDRI基因导入猪肾上皮细胞系LLC-PK_1,用跨细胞转运系统测定了P-糖蛋白对药物转运的影响。首次用一系列类固醇进行的研究表明,皮质醇和地塞米松是亲脂性相对较低的类固醇,它们能很好地被P-糖蛋白转运,但对P-糖蛋白介导的药物转运没有抑制作用。而亲脂性较强的类固醇则表现出较强的抑制作用,但它们不通过P-糖蛋白转运。其转运活性与抑制活性不一致,提示P-糖蛋白的转运机制具有多样性。下一步研究环孢素类似物对P-糖蛋白介导的SEV-…跨细胞转运的抑制作用更多的外周抗癌药物。亲脂性环孢素类似物抑制P-糖蛋白介导的柔红霉素、阿霉素和长春花碱的转运。抑制活性排序为SDZ PSC 833>、环孢素D、二氢环孢素D>、环孢素A>、环孢素C、二氢环孢素C。抗癌药物在细胞内的积累与P-糖蛋白的转运功能密切相关。抑制作用依赖于环孢素的浓度。对P-糖蛋白的抑制作用与其免疫抑制活性无关,而与其亲脂性有关。采用最强的药物SDZ PSC 833与阿霉素联合的I期研究,确定两种药物的最大耐受量,并研究药物在药代动力学中的相互作用。阿霉素清除量随SDZ PSC 833血药浓度升高而降低,提示抑制P-糖蛋白功能可改变药物的分布和消除。这些发现对于开发以P-糖蛋白为靶点的新的化疗药物是有用的。较少
英文摘要
To investigate a mechanism of drug transport by P-glycoprotein, a quantitative analysis has been performed for structure-activity relationships. The drug transport by P-glycoprotein was measured by a transcellular transport system by introducing human MDRI cDNA into a porcine kidney epithelial cell line, LLC-PK_1.The first study using a series of steroids showed that cortisol and dexamethasone, which are relatively lower lipophilic steroids, were well transported by P-glycoprotein, but that they did not possess an inhibitory effect on P-glycoprotein-mediated transport of drugs. On the other hand, steroids with higher lipophilicity showed a strong inhibitory effect, while they were not transported by P-glycoprotein. The transporting activity was not consistent with the inhibitory activity, suggesting a multiplicity of transporting mechanism of P-glycoprotein.The next study investigated the inhibitory effect of cyclosporin analogs on P-glycoprotein-mediated transcellular transport of sev … More eral anticancer agents. The lipophilic cyclosporin analogs inhibited P-glycoprotein-mediated transport of daunorubicin, doxorubicin and vinblastine. The rank order of the inhibitory activity was SDZ PSC 833 > cyclosporin D,dihydrocyclosporin D > cyclosporin A > cyclosporin C,dihydrocyclosporin C.The intracellular accumulation of the anticancer agents was highly associated with the transporting function of P-glycoprotein. The inhibitory effect depended on the concentration of cyclosporins. The inhibitory effect on P-glycoprotein was not correlated with the immunosuppressive activity, but was correlated with their lipophilicity.The phase I study of the combination of the most potent agent, SDZ PSC 833 and doxorubicin was conducted to determine the maximum tolerated dose of these two agents as well as to investigate the drug interaction in pharmacokinetics. The doxorubicin clearance was decreased with increased blood concentration of SDZ PSC 833, indicating that the inhibition of P-glycoprotein function could change drug distribution and elimination. These findings are useful for developing a new chemotherapy to target P-glycoprotein. Less
期刊论文(58)
专著(0)
科研奖励(0)
会议论文
登录
查看更多内容
堀 了平: "日本人における薬物動態母集団パラメータの推定(1):ジゴキシン" TDM研究. 11. 7-17 (1994)
Ryohei Hori:“日语药代动力学群体参数的估计(1):地高辛”TDM Research。11. 7-17 (1994)
DOI:
--
发表时间:
期刊:
影响因子:
--
作者:
[]
通讯作者:
Y.HASHIMOTO: "Population analysis of the dose-dependent pharmacokinetics of zonisamide in epileptic patients" Biological Pharmaceutical Bulletin. 17. 323-326 (1994)
Y.HASHIMOTO:“唑尼沙胺在癫痫患者中剂量依赖性药代动力学的群体分析”生物制药通报。
DOI:
--
发表时间:
期刊:
影响因子:
--
作者:
[]
通讯作者:
Y.Tanigawara: "Population Pharmacokinetics of Theophylline. III : Premarketing Study for a Once-Daily Administered Preparation" Biol.Pharm.Bull.18. 1590-1598 (1995)
Y.Tanikawara:“茶碱的群体药代动力学。III:每日一次给药制剂的上市前研究”Biol.Pharm.Bull.18。
DOI:
--
发表时间:
期刊:
影响因子:
--
作者:
[]
通讯作者:
D.Keppler: "Transport in the Liver". Kluwer Academic Publishers, 258 (1994)
D.Keppler:“肝脏中的运输”。
DOI:
--
发表时间:
期刊:
影响因子:
--
作者:
[]
通讯作者:
T.Iga: "Drug Interactions and Proper Use of Drugs". Yakugyo Jiho Sha, 486 (1996)
T.Iga:“药物相互作用和药物的正确使用”。
DOI:
--
发表时间:
期刊:
影响因子:
--
作者:
[]
通讯作者:
共 26 条
Proteomic and metabolomic analysis on chemo-sensitivity and resistance of cancer towards personalized medicine
-
批准号:23390037
-
项目类别:Grant-in-Aid for Scientific Research (B)
-
资助金额:$11.9万
-
财政年份:2011
-
负责人:TANIGAWARA Yusuke
-
依托单位:
Proteomic analysis for elucidation of individual differences in chemotherapeutic response and for biomarker development
-
批准号:20390049
-
项目类别:Grant-in-Aid for Scientific Research (B)
-
资助金额:$12.4万
-
财政年份:2008
-
负责人:TANIGAWARA Yusuke
-
依托单位:
Proteomic approach for personalized Medicine in cancer chemotherapy
-
批准号:18390053
-
项目类别:Grant-in-Aid for Scientific Research (B)
-
资助金额:$10.96万
-
财政年份:2006
-
负责人:TANIGAWARA Yusuke
-
依托单位:
Development of rational immunosuppressive therapy in organ transplantation based on pharmacogenomic and proteomic research
-
批准号:14370787
-
项目类别:Grant-in-Aid for Scientific Research (B)
-
资助金额:$8.9万
-
财政年份:2002
-
负责人:TANIGAWARA Yusuke
-
依托单位:
Development of Drug Monitoring System in Determining Optimal Dosage of Anticancer Drugs
-
批准号:12557234
-
项目类别:Grant-in-Aid for Scientific Research (B)
-
资助金额:$7.17万
-
财政年份:2000
-
负责人:TANIGAWARA Yusuke
-
依托单位:
Multiple analysis concerning therapeutic significance of drug-metabolizing enzyme CYP2C9 polymorphism
-
批准号:12672221
-
项目类别:Grant-in-Aid for Scientific Research (C)
-
资助金额:$1.98万
-
财政年份:2000
-
负责人:TANIGAWARA Yusuke
-
依托单位:
P-Glycoproten as a Molecular Target of Pharmacokinetic Studies for the Reversal of Multidrug Resistance
-
批准号:08672607
-
项目类别:Grant-in-Aid for Scientific Research (C)
-
资助金额:$1.41万
-
财政年份:1996
-
负责人:TANIGAWARA Yusuke
-
依托单位:
Biostatistical Modeling for Pharmacokinetics and Pharmacodynamics of Anticancer Agents and Application to Individualized Dosage Regimen
-
批准号:07557294
-
项目类别:Grant-in-Aid for Scientific Research (B)
-
资助金额:$0.38万
-
财政年份:1995
-
负责人:TANIGAWARA Yusuke
-
依托单位:
国内基金
海外基金
登录
查看更多内容
汉防己甲素协同维拉帕米靶向MDR-1/P-糖蛋白逆转T细胞多药耐药的药效及分子机制研究
-
批准号:JCZRLH202600483
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2026
-
负责人:
-
依托单位:
基于MB-MDR分析模型的同型半胱氨酸代谢异常与动脉硬化多维度关联研究
-
批准号:2025JJ70491
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2025
-
负责人:谭碧峰
-
依托单位:
基于溶酶体逃逸增效构建GLUT1介导的级联靶向脂质体及其抗颅内
MDR-AB菌胞内感染研究
-
批准号:
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2024
-
负责人:肖维
-
依托单位:
基于超分子自组装构建多途径逆转肿瘤MDR的靶向纳米递药体系用于增强抗癌疗效
-
批准号:22301246
-
项目类别:青年科学基金项目
-
资助金额:30万元
-
批准年份:2023
-
负责人:晁爽
-
依托单位:
基于MDR-PTB病证生物学等多维动态数据联合多模态深度学习探索气阴虚证治规律
-
批准号:
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2023
-
负责人:张顺先
-
依托单位:
MDR/Pre-XDR/XDR分枝杆菌的适应性代价和补偿性进化研究
-
批准号:2023JJ40007
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2023
-
负责人:皮锐
-
依托单位:
基于“调和寒热”理论构建逆转乳腺癌MDR的“寒性中药-光动力-光热”递药系统
-
批准号:82304908
-
项目类别:青年科学基金项目
-
资助金额:30万元
-
批准年份:2023
-
负责人:任维
-
依托单位:
HnRNPK胞浆转位稳定MDR1mRNA参与胃癌细胞耐药的机制研究
-
批准号:2023JJ30521
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2023
-
负责人:曾颖
-
依托单位:
内生尤韦可拟盘多毛孢中新颖苯丙素苷类P-gp抑制剂的发现及其肿瘤MDR逆转机制研究
-
批准号:--
-
项目类别:青年科学基金项目
-
资助金额:30万元
-
批准年份:2022
-
负责人:钱一鑫
-
依托单位:
LHBs对MDR1的调控及其在HBV转录、复制和肝细胞增殖转化中的作用机制研究
-
批准号:
-
项目类别:省市级项目
-
资助金额:--
-
批准年份:2022
-
负责人:李世颖
-
依托单位: