The ability of verapamil to restore intracellular accumulation of anthracyclines in multidrug resistant cells depends on the kinetics of their uptake

维拉帕米 柔红霉素 P-糖蛋白 去甲柔比星 流出 药理学 多重耐药 蒽环类 亲脂性 细胞内 吡柔比星 化学 生物化学 生物 化疗 内科学 医学 阿糖胞苷 抗生素 有机化学 乳腺癌 癌症
作者
Samlee Mankhetkorn,Arlette Garnier‐Suillerot
出处
期刊:European Journal of Pharmacology [Elsevier]
卷期号:343 (2-3): 313-321 被引量:39
标识
DOI:10.1016/s0014-2999(97)01548-3
摘要

The basic distinguishing feature of all cells expressing functional P-glycoprotein-multidrug resistance is a decrease of steady state drug levels as compared to those in drug-sensitive controls. A variety of small molecules, such as verapamil and cyclosporin A, bind to P-glycoprotein and inhibit its ability to pump out antitumor drugs. The kinetics of P-glycoprotein-mediated efflux of various anthracycline derivatives was measured in multidrug-resistant (MDR) K562 cells in the presence of verapamil. Used for the purpose were daunorubicin, idarubicin and 8-S-fluoro-idarubicin which have the same pKa of deprotonation equal to 8.4, but different lipophilicity, 4′-epi-2′-bromo-daunorubicin which has a lipophilicity which is comparable to that of daunorubicin but a pKa equal to 6.3, pirarubicin with pKa equal to 7.7 and lipophilicity different from that of these derivatives were used. Our data show (1) that verapamil is unable to completely block the P-glycoprotein-mediated efflux of anthracyclines and that 10% of its functionality remains even with high verapamil concentrations, (2) that the ability of verapamil to restore intracellular accumulation of anthracyclines in MDR cells depends on the kinetics of their uptake. With fast kinetics uptake, as is the case for idarubicin, 8-S-fluoro-idarubicin, 4′-epi-2′-bromo-daunorubicin and pirarubicin (which have either a low pKa and/or high lipophilicity), verapamil can restore in multidrug resistant cells an intracellular drug level which is comparable to that observed in sensitive cells. This is not possible when the kinetics of uptake is low as is the case for daunorubicin. Cyclosporin A is a more potent modulator and is able to fully restore daunorubicin accumulation in multidrug resistant cells.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
NexusExplorer应助Rio采纳,获得10
刚刚
李爱国应助Phi.Wang采纳,获得10
1秒前
mz完成签到 ,获得积分10
2秒前
2秒前
kcul完成签到 ,获得积分10
4秒前
桐桐应助邹友亮采纳,获得10
6秒前
落梦关注了科研通微信公众号
7秒前
8秒前
Yvonna发布了新的文献求助10
8秒前
babyhead完成签到,获得积分10
9秒前
blwd发布了新的文献求助50
9秒前
恍恍惚惚完成签到,获得积分10
10秒前
养猪人完成签到,获得积分10
10秒前
可爱女人完成签到 ,获得积分10
10秒前
11秒前
上官子默完成签到,获得积分10
11秒前
无聊的熠彤完成签到 ,获得积分10
11秒前
sunny完成签到,获得积分10
13秒前
小呆发布了新的文献求助10
14秒前
15秒前
圆圆圆完成签到 ,获得积分10
16秒前
zenmefeishi完成签到,获得积分10
16秒前
Phi.Wang发布了新的文献求助10
17秒前
zjuszk完成签到 ,获得积分10
17秒前
阿冰完成签到,获得积分10
18秒前
AC赵先生完成签到,获得积分10
20秒前
乐观沛白完成签到,获得积分20
22秒前
slf完成签到,获得积分10
24秒前
24秒前
月儿完成签到,获得积分10
24秒前
Jay完成签到,获得积分10
26秒前
小呆完成签到,获得积分10
26秒前
27秒前
shelly发布了新的文献求助10
27秒前
yy完成签到 ,获得积分10
27秒前
龘龘完成签到,获得积分10
28秒前
李安全完成签到,获得积分10
28秒前
29秒前
虾502发布了新的文献求助10
29秒前
岁岁完成签到,获得积分10
29秒前
高分求助中
Evolution 10000
ISSN 2159-8274 EISSN 2159-8290 1000
Becoming: An Introduction to Jung's Concept of Individuation 600
Ore genesis in the Zambian Copperbelt with particular reference to the northern sector of the Chambishi basin 500
A new species of Coccus (Homoptera: Coccoidea) from Malawi 500
A new species of Velataspis (Hemiptera Coccoidea Diaspididae) from tea in Assam 500
PraxisRatgeber: Mantiden: Faszinierende Lauerjäger 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3162769
求助须知:如何正确求助?哪些是违规求助? 2813701
关于积分的说明 7901715
捐赠科研通 2473342
什么是DOI,文献DOI怎么找? 1316778
科研通“疑难数据库(出版商)”最低求助积分说明 631516
版权声明 602175