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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.

SUBMITTER: Piedade R

PROVIDER: S-EPMC4291335 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Carboxymefloquine, the major metabolite of the antimalarial drug mefloquine, induces drug-metabolizing enzyme and transporter expression by activation of pregnane X receptor.

Piedade Rita R Traub Stefanie S Bitter Andreas A Nüssler Andreas K AK Gil José P JP Schwab Matthias M Burk Oliver O

Antimicrobial agents and chemotherapy 20141013 1

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 ...[more]

PMID: 25313206

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Project description:BackgroundAppropriate interactions between antiretroviral therapies (ART) and drug transporters and metabolizing enzymes at the blood brain barrier (BBB) are critical to ensure adequate dosing of the brain to achieve HIV suppression. These proteins are modulated by demographic and lifestyle factors, including substance use. While understudied, illicit substances share drug transport and metabolism pathways with ART, increasing the potential for adverse drug:drug interactions. This is particularly important when considering the brain as it is relatively undertreated compared to peripheral organs and is vulnerable to substance use-mediated damage.MethodsWe used an in vitro model of the human BBB to determine the extravasation of three first-line ART drugs, emtricitabine (FTC), tenofovir (TFV), and dolutegravir (DTG), in the presence and absence of cocaine, which served as our illicit substance model. The impact of cocaine on BBB integrity and permeability, drug transporters, metabolizing enzymes, and their master transcriptional regulators were evaluated to determine the mechanisms by which substance use impacted ART central nervous system (CNS) availability.ResultsWe determined that cocaine had a selective impact on ART extravasation, where it increased FTC's ability to cross the BBB while decreasing TFV. DTG concentrations that passed the BBB were below quantifiable limits. Interestingly, the potent neuroinflammatory modulator, lipopolysaccharide, had no effect on ART transport, suggesting a specificity for cocaine. Unexpectedly, cocaine did not breach the BBB, as permeability to albumin and tight junction proteins and adhesion molecules remained unchanged. Rather, cocaine selectively decreased the pregnane-x receptor (PXR), but not constitutive androstane receptor (CAR). Consequently, drug transporter expression and activity decreased in endothelial cells of the BBB, including p-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 4 (MRP4). Further, cytochrome P450 3A4 (CYP3A4) enzymatic activity increased following cocaine treatment that coincided with decreased expression. Finally, cocaine modulated adenylate kinases are required to facilitate biotransformation of ART prodrugs to their phosphorylated, pharmacologically active counterparts.ConclusionOur findings indicate that additional considerations are needed in CNS HIV treatment strategies for people who use cocaine, as it may limit ART efficacy through regulation of drug transport and metabolizing pathways at the BBB.

Project description:The aim of the present study was to evaluate whether quercetin (Que) modulates the mRNA and protein expression levels of drug‑metabolizing enzymes (DMEs) and drug transporters (DTs) in the small intestine and liver, and thus modifies the pharmacokinetic profile of cyclosporine (CsA) in rats. This two‑part study evaluated the pharmacokinetic profiles of CsA in the presence or absence of Que (experiment I) and the involvement of DMEs and DTs (experiment II). In experiment I, 24 rats received single‑dose CsA (10 mg/kg) on day 1, single‑dose Que (25, 50 and 100 mg/kg/day; eight rats in each group) on days 3‑8, and concomitant CsA/Que on day 9. In experiment II, the mRNA and protein expression levels of cytochrome P (CYP)3A1, CYP3A2, UDP glucuronosyltransferase family 1 member A complex locus, organic anion‑transporting polypeptide (OATP)2B1, OATP1B2, P‑glycoprotein, breast cancer resistance protein, and multidrug resistance‑associated protein 2 in the small intestine and liver of rats were analyzed following oral administration of Que at 25, 50 and 100 mg/kg in the presence or absence of CsA (10 mg/kg) for seven consecutive days. Co‑administration of Que (25,50 and 100 mg/kg) decreased the maximum serum concentration of CsA by 46, 50 and 47% in a dose‑independent manner. In addition, the area under the curve to the last measurable concentration and area under the curve to infinite time were decreased, by 21 and 16%, 30 and 33%, and 33 and 34% (P<0.01), respectively. However, the mRNA and protein expression levels of the above‑mentioned DMEs and DTs were inhibited by Que in a dose‑dependent manner (P<0.01) to a similar extent in the small intestine and liver. It was demonstrated that Que was able to reduce the bioavailability of CsA following multiple concomitant doses in rats. Overlapping modulation of intestinal and hepatic DMEs and DTs, as well as the DME‑DT interplay are potential explanations for these observations.

Dataset Information

Carboxymefloquine, the major metabolite of the antimalarial drug mefloquine, induces drug-metabolizing enzyme and transporter expression by activation of pregnane X receptor.

Publications

Carboxymefloquine, the major metabolite of the antimalarial drug mefloquine, induces drug-metabolizing enzyme and transporter expression by activation of pregnane X receptor.

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