title: Carboxymefloquine, the major metabolite of the antimalarial drug mefloquine, induces drug-metabolizing enzyme and transporter expression by activation of pregnane X receptor.
abstract: 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.
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: Rita
authors.initials: R
authors.lastname: Piedade
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Traub
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bitter
authors.affiliation: Department of Traumatology, University of Tübingen, Tübingen, Germany.
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Nüssler
authors.affiliation: Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden Drug Resistance and Pharmacogenetics, Center for Biodiversity, Functional and Integrative Genomics, Faculdade de Ciências, Universidade de Lisboa, Lisbon, Portugal Harpur College of Arts and Sciences, Binghamton University, The State University of New York, Binghamton, New York, USA.
authors.forename: José P
authors.initials: JP
authors.lastname: Gil
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany Department of Clinical Pharmacology, Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany oliver.burk@ikp-stuttgart.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Burk
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D065702:Cytochrome P-450 CYP2B6 / Q000378:metabolism; D065695:Cytochrome P-450 CYP2B6 Inducers / Q000494:pharmacology*; D004347:Drug Interactions; D004351:Drug Resistance; D056945:Hep G2 Cells; D022781:Hepatocytes; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D015767:Mefloquine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D000077297:Pregnane X Receptor; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering; D011987:Receptors, Steroid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D000962:Antimalarials; D065695:Cytochrome P-450 CYP2B6 Inducers; D000077297:Pregnane X Receptor; D034741:RNA, Small Interfering; D011987:Receptors, Steroid; C057006:Ro 21-5104; D065702:Cytochrome P-450 CYP2B6; D015767:Mefloquine