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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<jats:italic>in vitro<\/jats:italic>findings are of<jats:italic>in vivo<\/jats:italic>relevance has to be addressed in future clinical drug-drug interaction studies.<\/jats:p>","DOI":"10.1128\/aac.04140-14","type":"journal-article","created":{"date-parts":[[2014,10,14]],"date-time":"2014-10-14T03:23:42Z","timestamp":1413257022000},"page":"96-104","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":25,"title":["Carboxymefloquine, the Major Metabolite of the Antimalarial Drug Mefloquine, Induces Drug-Metabolizing Enzyme and Transporter Expression by Activation of Pregnane X Receptor"],"prefix":"10.1128","volume":"59","author":[{"given":"Rita","family":"Piedade","sequence":"first","affiliation":[{"name":"Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefanie","family":"Traub","sequence":"additional","affiliation":[{"name":"Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Bitter","sequence":"additional","affiliation":[{"name":"Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas K.","family":"N\u00fcssler","sequence":"additional","affiliation":[{"name":"Department of Traumatology, University of T\u00fcbingen, T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 P.","family":"Gil","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden"},{"name":"Drug Resistance and Pharmacogenetics, Center for Biodiversity, Functional and Integrative Genomics, Faculdade de Ci\u00eancias, Universidade de Lisboa, Lisbon, Portugal"},{"name":"Harpur College of Arts and Sciences, Binghamton University, The State University of New York, Binghamton, New York, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Schwab","sequence":"additional","affiliation":[{"name":"Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany"},{"name":"Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital T\u00fcbingen, T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver","family":"Burk","sequence":"additional","affiliation":[{"name":"Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.30875\/c5be4728-en"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1586\/ecp.13.17"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.3855\/jidc.2703"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200140050-00003"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(03)00092-4"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1472-8206.2007.00471.x"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.112.045765"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2009.04.002"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.62.3.638"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.2012.685237"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.104.009019"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2362.2006.01700.x"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2012.02033.x"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1186\/1478-1336-2-1"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1186\/1478-1336-3-3"},{"key":"e_1_3_2_17_2","first-page":"1454","article-title":"Natural protein variants of pregnane X receptor with altered transactivation activity toward CYP3A4","volume":"29","author":"Hustert E","year":"2001","unstructured":"Hustert E, Zibat A, Presecan-Siedel E, Eiselt R, Mueller R, Fuss C, Brehm I, Brinkmann U, Eichelbaum M, Wojnowski L, Burk O. 2001. 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