Interactions of attention-deficit/hyperactivity disorder therapeutic agents with the efflux transporter P-glycoprotein.
Interactions of attention-deficit/hyperactivity disorder therapeutic agents with the efflux transporter P-glycoprotein.
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注意力缺陷/多动症治疗药物与外排转运蛋白 P-糖蛋白的相互作用。
DOI：
10.1016/j.ejphar.2007.09.035
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发表时间：
2008
影响因子：
5
通讯作者：
Markowitz,JohnS
中科院分区：
文献类型：
--
作者：
Zhu,Hao-Jie;Wang,Jun-Sheng;Donovan,JenniferL;Jiang,Yan;Gibson,BryanB;DeVane,CLindsay;Markowitz,JohnS
本研究的目的是利用已建立的体外试验评估药物转运蛋白P-糖蛋白与注意力缺陷/多动障碍（ADHD）治疗药物托莫西汀以及哌甲酯、苯丙胺和莫达非尼的单个异构体之间的潜在相互作用。初始ATP酶测定表明，d-和l-哌甲酯对P-糖蛋白具有弱亲和力。测定P-糖蛋白底物阿霉素和罗丹明123在P-糖蛋白过表达细胞系LLC-PK 1/MDR 1中的细胞内蓄积，以评价对P-糖蛋白的潜在抑制作用。结果表明，除了两种莫达非尼异构体外，所有化合物在较高浓度下均显著增加多柔比星和罗丹明123在LLC-PK 1/MDR 1细胞中的蓄积。为了研究P-糖蛋白底物性质，在存在和不存在P-糖蛋白抑制剂PSC 833的情况下测量了LLC-PK 1/MDR 1和P-糖蛋白阴性LLC-PK 1细胞中测试化合物的细胞内浓度。结果表明，d-哌甲酯在LLC-PK 1细胞中的蓄积比LLC-PK 1/MDR 1细胞中高32.0%。此外，在LLC-PK 1/MDR 1细胞中，PSC 833的联合给药导致d-莫达非尼和l-莫达非尼蓄积分别增加52.9%和45.6%。进一步的研究表明，L-modafinil在LLC-PK 1/MDR 1细胞单层中的基底外侧至顶端（B-A）方向转运显著高于顶端至基底外侧（A-B）方向。PSC 833处理显著降低了l-莫达非尼在B-A方向的转运。总之，我们的研究结果表明，所有测试的代理商与莫达非尼异构体的例外是相对较弱的P-糖蛋白抑制剂。此外，P-糖蛋白可能在d-哌甲酯、d-莫达非尼和l-莫达非尼的转运中起次要作用。
The objective of this study was to assess the potential interactions of the drug transporter P-glycoprotein with attention-deficit/hyperactivity disorder (ADHD) therapeutic agents atomoxetine — and the individual isomers of methylphenidate, amphetamine, and modafinil utilizing established in vitro assay. An initial ATPase assay indicated that both d- and l-methylphenidate have weak affinity for P-glycoprotein. The intracellular accumulation of P-glycoprotein substrates doxorubicin and rhodamine123 in the P-glycoprotein overexpressing cell line LLC-PK1/MDR1 was determined to evaluate potential inhibitory effects on P-glycoprotein. The results demonstrated that all compounds, except both modafinil isomers, significantly increased doxorubicin and rhodamine123 accumulation in LLC-PK1/MDR1 cells at higher concentrations. To investigate the P-glycoprotein substrate properties, the intracellular concentrations of the tested compounds in LLC-PK1/MDR1 and P-glycoprotein negative LLC-PK1 cells were measured in the presence and absence of the P-glycoprotein inhibitor PSC833. The results indicate that the accumulation of d-methylphenidate in LLC-PK1 cells was 32.0% higher than in LLC-PK1/MDR1 cells. Additionally, coadministration of PSC833 leads to 52.9% and 45.6% increases in d-modafinil and l-modafinil accumulation, respectively, in LLC-PK1/MDR1 cells. Further studies demonstrated that l-modafinil transport across LLC-PK1/MDR1 cell monolayers in the basolateral-to-apical (B–A) direction was significantly higher than in the apical-to-basolateral (A–B) direction. PSC833 treatment significantly decreased the transport of l-modafinil in B–A direction. In conclusion, our results suggest that all tested agents with the exception of modafinil isomers are relatively weak P-glycoprotein inhibitors. Furthermore, P-glycoprotein may play a minor role in the transport of d-methylphenidate, d-modafinil, and l-modafinil.