Piedade Rita, Traub Stefanie, Bitter Andreas, Nüssler Andreas K, Gil José P, Schwab Matthias, Burk Oliver
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
Department of Traumatology, University of Tübingen, Tübingen, Germany.
Antimicrob Agents Chemother. 2015 Jan;59(1):96-104. doi: 10.1128/AAC.04140-14. Epub 2014 Oct 13.
Malaria patients are frequently coinfected with HIV and mycobacteria causing tuberculosis, which increases the use of coadministered drugs and thereby enhances the risk of pharmacokinetic drug-drug interactions. Activation of the pregnane X receptor (PXR) by xenobiotics, which include many drugs, induces drug metabolism and transport, thereby resulting in possible attenuation or loss of the therapeutic responses to the drugs being coadministered. While several artemisinin-type antimalarial drugs have been shown to activate PXR, data on nonartemisinin-type antimalarials are still missing. Therefore, this study aimed to elucidate the potential of nonartemisinin antimalarial drugs and drug metabolites to activate PXR. We screened 16 clinically used antimalarial drugs and six major drug metabolites for binding to PXR using the two-hybrid PXR ligand binding domain assembly assay; this identified carboxymefloquine, the major and pharmacologically inactive metabolite of the antimalarial drug mefloquine, as a potential PXR ligand. Two-hybrid PXR-coactivator and -corepressor interaction assays and PXR-dependent promoter reporter gene assays confirmed carboxymefloquine to be a novel PXR agonist which specifically activated the human receptor. In the PXR-expressing intestinal LS174T cells and in primary human hepatocytes, carboxymefloquine induced the expression of drug-metabolizing enzymes and transporters on the mRNA and protein levels. The crucial role of PXR for the carboxymefloquine-dependent induction of gene expression was confirmed by small interfering RNA (siRNA)-mediated knockdown of the receptor. Thus, the clinical use of mefloquine may result in pharmacokinetic drug-drug interactions by means of its metabolite carboxymefloquine. Whether these in vitro findings are of in vivo relevance has to be addressed in future clinical drug-drug interaction studies.
疟疾患者常合并感染人类免疫缺陷病毒（HIV）和导致结核病的分枝杆菌，这增加了联合用药的使用，从而提高了药代动力学药物相互作用的风险。包括许多药物在内的外源性物质激活孕烷X受体（PXR）会诱导药物代谢和转运，从而可能导致对联合使用药物的治疗反应减弱或丧失。虽然几种青蒿素类抗疟药物已被证明可激活PXR，但关于非青蒿素类抗疟药物的数据仍然缺失。因此，本研究旨在阐明非青蒿素类抗疟药物及其药物代谢物激活PXR的潜力。我们使用双杂交PXR配体结合域组装试验筛选了16种临床使用的抗疟药物和6种主要药物代谢物与PXR的结合情况；结果确定抗疟药物甲氟喹的主要且无药理活性的代谢物羧基甲氟喹为潜在的PXR配体。双杂交PXR共激活剂和共抑制因子相互作用试验以及PXR依赖性启动子报告基因试验证实羧基甲氟喹是一种新型的PXR激动剂，可特异性激活人类受体。在表达PXR的肠道LS174T细胞和原代人肝细胞中，羧基甲氟喹在mRNA和蛋白质水平上诱导药物代谢酶和转运蛋白的表达。通过小干扰RNA（siRNA）介导的受体敲低证实了PXR对羧基甲氟喹依赖性基因表达诱导的关键作用。因此，甲氟喹的临床使用可能因其代谢物羧基甲氟喹而导致药代动力学药物相互作用。这些体外研究结果是否具有体内相关性，还有待未来的临床药物相互作用研究加以探讨。
