St John's Wort increases expression of P-glycoprotein: Implications for drug interactions
St John's Wort increases expression of P-glycoprotein: Implications for drug interactions
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DOI：
10.1046/j.0306-5251.2001.01516.x
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发表时间：
2002-01-01
影响因子：
3.4
通讯作者：
Feely, J
中科院分区：
文献类型：
--
作者：
Hennessy, M;Kelleher, D;Feely, J
圣约翰草（SJW）被广泛用于治疗抑郁症，但人们担心它可能与其他药物相互作用。与SJW联合给药导致茚地那韦和环孢素的血浆谷浓度显著降低[1，2]。细胞色素P450 3A 4（CYP 3A 4）的诱导被认为是最可能的相互作用机制。然而，在临床实践中观察到的相互作用的程度大于体外研究预测的程度，表明可能存在其他相互作用机制。由于茚地那韦和环孢菌素的底物CYP 3A 4和多药转运蛋白P-糖蛋白，我们假设，调制的P-糖蛋白的表达和功能，SJW可能有助于发展潜在的有害药物-药物interactions.Methods健康志愿者被随机分配到SJW（0.15%）600毫克，每天三次，16天（n=15）或安慰剂（n=7）。在基线、治疗后第16天和第32天采集血样，用于P-糖蛋白表达和功能。通过Ficoll密度梯度离心分离外周血淋巴细胞（PBMC），固定并透化。细胞用P-糖蛋白特异性抗体染色，通过流式细胞术定量，并获得中值荧光强度（MFI）值。波形蛋白和IE（无义抗体）用作对照。RT-PCR证实MDR 1基因产物的存在。P-糖蛋白介导的药物外排被确定为罗丹明外排在利托那韦的存在和不存在的功能。数据表示为平均值+/-s. d。结果SJW治疗组P-糖蛋白表达较基线增加4.2倍（7.0 ± 1.9 vs 29.5 ± 14.3（MFI）; P
Aims St John's Wort (SJW) is widely used in the treatment of depression but concerns have been raised about its potential to interact with other drugs. Co-administration with SJW has resulted in significant reductions in trough plasma concentrations of indinavir and cyclosporin [1, 2]. Induction of cytochrome P450 3A4 (CYP3A4) has been implicated as the most likely interaction mechanism. However, the magnitude of the interaction seen in clinical practice is greater than that predicted by in vitro studies suggesting additional interaction mechanisms may exist. As indinavir and cyclosporin are substrates for both CYP3A4 and the multi drug transporter P-glycoprotein we hypothesized that modulation of P-glycoprotein expression and function by SJW may contribute to the development of potentially harmful drug-drug interactions.Methods Healthy volunteers were randomized to either SJW (0.15%) 600 mg three times daily for 16 days (n=15) or placebo (n=7). Blood samples were obtained for P-glycoprotein expression and function at baseline, 16 and 32 days post treatment. Peripheral blood lymphocytes (PBMCs) were isolated by Ficoll density gradient centrifugation, fixed and permeabilized. Cells were stained with a P-glycoprotein specific antibody, quantified by flow cytometry and median fluorescence intensity (MFI) values obtained. Vimentin and IE (nonsense antibody) were used as controls. The presence of the MDR 1 gene product was confirmed by RT-PCR. P-glycoprotein mediated drug efflux was determined as a function of rhodamine efflux in the absence and presence of ritonavir. Data are expressed as mean+/-s.d. and were subjected to nonparametric analysis.Results P-glycoprotein expression increased 4.2 fold from baseline in subjects treated with SJW (7.0+/-1.9 vs 29.5+/-14.3 (MFI); P