Ibrahim S, Peggins J, Knapton A, Licht T, Aszalos A
Office of Clinical Pharmacology and Biopharmaceutics, Food and Drug Administration, HFD 860, 5600 Fishers Lane, Rockville, MD 20857, USA.
Anticancer Res. 2001 Mar-Apr;21(2A):847-56.
Treatment of patients with several drugs simultaneously may result in modulation of the naturally expressed P-glycoprotein (Pgp) at different tissues. With this possibility in mind, we have assessed the ability of different classes of drugs to modulate Pgp function in vitro. Modulation of the Pgp function was studied at in vitro drug concentrations comparable to therapeutic blood levels of the drugs.
Human blood brain barrier endothelial cells and human colon adenocarcinoma cells were transduced or transfected with the multidrug resistance gene (MDR1) to express Pgp. The uptake of fluorescent substrates of Pgp, Rhodamine 123 and daunorubicin, into these cells and NIH3T3/MDR1 and MDCK/MDR1 cells was measured by flow cytometry and in monolayers in the presence and absence of the different drugs.
From the tested six H1-receptor blockers, seven beta-adrenergic antagonists, four analgesics, ten diuretics and five quinolons, five drugs inhibited Pgp at therapeutic blood levels and two at somewhat higher concentrations. Significant synergism for blocking Pgp could be demonstrated for several drugs.
We conclude that administration of several drugs which modulate the function of Pgp to patients may adversely affect the natural function of this efflux pump and may cause drug-drug interactions induced side effects.
同时使用多种药物治疗患者可能会导致不同组织中天然表达的P-糖蛋白（Pgp）受到调节。考虑到这种可能性，我们评估了不同类别的药物在体外调节Pgp功能的能力。在与药物治疗血药浓度相当的体外药物浓度下研究了Pgp功能的调节。
用人多药耐药基因（MDR1）转导或转染人血脑屏障内皮细胞和人结肠腺癌细胞以表达Pgp。通过流式细胞术并在单层细胞中，在存在和不存在不同药物的情况下，测量Pgp的荧光底物罗丹明123和柔红霉素进入这些细胞以及NIH3T3/MDR1和MDCK/MDR1细胞的摄取情况。
在所测试的六种H1受体阻滞剂、七种β-肾上腺素能拮抗剂、四种镇痛药、十种利尿剂和五种喹诺酮类药物中，有五种药物在治疗血药浓度下抑制Pgp，两种在稍高浓度下抑制。几种药物对阻断Pgp具有显著的协同作用。
我们得出结论，给患者使用几种调节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，并可能导致药物相互作用引起的副作用。
