Ibrahim S, Peggins J, Knapton A, Licht T, Aszalos A
Office of Clinical Pharmacology and Biopharmaceutics, Food and Drug Administration, Rockville, Maryland 20857, USA.
J Pharmacol Exp Ther. 2000 Dec;295(3):1276-83.
We investigated the effect of antiemetic, antipsychotic, and Ca(2+) blocker drugs on the function of P-glycoprotein (Pgp) in vitro and compared inhibitory concentrations with therapeutic blood levels. Human colon adenocarcinoma (Caco-2) and human blood-brain barrier endothelial cells were transfected or transduced to express Pgp, and the uptake of rhodamine123, calcein AM, or daunorubicin was measured by flow cytometry in the presence of the drugs. NIH3T3/MDR1 cells were used for reference testing. Results of the flow cytometric studies were supported by cell proliferation and monolayer permeability studies. Thirty-five drugs are included in this study, of which 13 modulate the function of Pgp at the therapeutic blood concentration and 8 at a concentration 2 to 4 times higher. Two drugs, which block the function of Pgp only partially at therapeutic blood concentrations, blocked the function of Pgp completely if used concomitantly. Based on these in vitro experiments, we conclude that administration of several drugs that modulate the function of Pgp simultaneously may adversely affect the natural function of this efflux pump and may cause drug-induced side effects in patients.
我们在体外研究了止吐药、抗精神病药和钙通道阻滞剂对P-糖蛋白（Pgp）功能的影响，并将抑制浓度与治疗血药浓度进行了比较。对人结肠腺癌（Caco-2）细胞和人血脑屏障内皮细胞进行转染或转导以表达Pgp，并在药物存在的情况下通过流式细胞术测定罗丹明123、钙黄绿素AM或柔红霉素的摄取。使用NIH3T3/MDR1细胞进行参考测试。流式细胞术研究结果得到细胞增殖和单层通透性研究的支持。本研究纳入了35种药物，其中13种在治疗血药浓度下调节Pgp的功能，8种在浓度高出2至4倍时调节其功能。有两种药物在治疗血药浓度下仅部分阻断Pgp的功能，但如果同时使用则可完全阻断其功能。基于这些体外实验，我们得出结论，同时给予几种调节Pgp功能的药物可能会对这种外排泵的天然功能产生不利影响，并可能导致患者出现药物诱导的副作用。
