Carboxymefloquine, the Major Metabolite of the Antimalarial Drug Mefloquine, Induces Drug-Metabolizing Enzyme and Transporter Expression by Activation of Pregnane X Receptor

Abstract

f 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. M alaria, which is caused by infection with parasitic protozoans of the genus Plasmodium, is still a major global health burden, with an estimated 207 million cases and 627,000 deaths worldwide in 2012 (1). The emerging resistance of the parasite to artemisinins (2) and the need to treat malaria patients coinfected with HIV and/or mycobacteria causing tuberculosis (3) increasingly necessitates the use of combination drug therapies and coadministration of drugs, respectively, which also may be accompanied by a higher risk for drug-drug interactions. Mechanistically, these may arise from the inhibition or induction of metabolism and/or transport of coadministered drugs. Competitive or noncompetitive enzyme inhibition may result in adverse toxic effects due to higher-than-expected drug concentrations, whereas clinically relevant induction may result in therapeutic failure due to insufficient drug levels. The interaction potential of antimalarial drugs due to the inhibition of cytochrome P450 (CYP) drugmetabolizing enzymes has been analyzed quite extensively in vitro, and it has been shown to result in some clinically relevant drugdrug interactions, as exemplified...

Pharmacokinetics of mefloquine and its effect on sulfamethoxazole and trimethoprim steady-state blood levels in intermittent preventive treatment (IPTp) of pregnant HIV-infected women in Kenya

“…The half-life for carboxymefloquine of 21 days [ 35 ] corresponds to the doubling time of SMX of 19 days, suggesting that the presence of the carboxymefloquine metabolite may influence SMX metabolism. A recent study has shown that the major metabolite of MQ, carboxymefloquine induces the expression of drug metabolizing enzymes and transporters by activating the pregnane X receptor [ 37 ].…”

Nelfinavir and Its Active Metabolite M8 Are Partial Agonists and Competitive Antagonists of the Human Pregnane X Receptor

“…Eukaryotic expression plasmids encoding full-length human nuclear receptors PXR (Geick et al, 2001), constitutive androstane receptor (CAR) 1 (Burk et al 2002) and CAR3 (Arnold et al 2004), thyroid hormone receptor (THR) α1, THRβ1, vitamin D receptor (VDR) (Burk et al, 2005), liver X receptor (LXR) α and LXRβ (Piedade et al 2015) have all been described. Expression plasmids encoding the human small PXR variant, which consists of the ligand binding domain (amino acids 113-434) only (Jeske et al, 2017), and PXR mutant S208W/S247W/C284W (Burk et al, 2018) have already been described.…”

Contribution of Major Metabolites toward Complex Drug-Drug Interactions of Deleobuvir: In Vitro Predictions and In Vivo Outcomes

“…Structurally similar metabolites have been shown to possess similar or lower potency of induction (Petzer et al, 2003;Medina-Diaz et al, 2009). One recent report highlighted carboxymefloquine as being a pregnane X receptor (PXR) ligand, whereas the parent mefloquine was not (Piedade et al, 2015). With deleobuvir, reduction of an alkene to form CD 6168 resulted in a potent inducer.…”