Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers

Ridtitid, Wibool; Wongnawa, Malinee; Mahatthanatrakul, Werawath; Raungsri, Nuntida; Sunbhanich, Methi

doi:10.1111/j.1365-2710.2005.00651.x

Cited by 49 publications

(23 citation statements)

References 19 publications

(27 reference statements)

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“…A number of studies have demonstrated that coadministration of metabolic inhibitors can enhance the pharmacokinetic profile of antiparasitic drugs and so − no noticeable disruption, + general/mild disruption, ++ severe disruption, +++ very severe disruption, KTZ ketoconazole, NADPH nicotinamide adenine dinucleotide phosphate, TCBZ triclabendazole, TCBZ.SO triclabendazole sulphoxide increase their bioavailability: studies not just on benzimidazoles (Luder et al 1986;Bekhti and Pirotte 1987;Wen et al 1996;Prichard 1991, 1992a, b;Lanusse et al 1992;López-García et al 1998;McKellar et al 2002;Sánchez et al 2002;Merino et al 2003a, b), but on other compounds such as macrocyclic lactones (Hugnet et al 2007;Alvinerie et al 2008), the anti-schistosomal drug, praziquantel (Diekmann et al 1989;Ridtitid et al 2007) and the anti-malarial, mefloquine (Ridtitid et al 2005;Wisedpanichkij et al 2009). The potentiation of drug availability observed has lead a number of workers to propose the use of such drug combinations as a strategy to deal with drug resistance (Lanusse and Prichard 1993;Lanusse et al 1995;Benchaoui and McKellar 1996;Dupuy et al 2003;Sánchez-Bruni et al 2005;Alvinerie et al 2008;Wisedpanichkij et al 2009).…”

Section: Discussionmentioning

confidence: 98%

Enhancement of the drug susceptibility of a triclabendazole-resistant isolate of Fasciola hepatica using the metabolic inhibitor ketoconazole

et al. 2010

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A study has been carried out to investigate whether the action of triclabendazole (TCBZ) is altered by using the metabolic inhibitor, ketoconazole (KTZ) to inhibit the cytochrome P450 (CYP 450) system within Fasciola hepatica. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The CYP 450 enzyme system was inhibited by a 2 h pre-incubation in KTZ (40 microM). Flukes were then incubated for a further 22 h in NCTC medium containing either KTZ; KTZ + nicotinamide adenine dinucleotide phosphate (NADPH; 1 nM); KTZ + NADPH + TCBZ (15 microg/ml); or KTZ + NADPH + triclabendazole sulphoxide (TCBZ.SO;15 microg/ml). Morphological changes resulting from drug treatment and following metabolic inhibition were assessed using scanning electron microscopy. After treatment with either TCBZ or TCBZ.SO alone, there was greater disruption to the TCBZ-susceptible isolate than the TCBZ-resistant isolate. However, co-incubation with KTZ and TCBZ/TCBZ.SO led to more severe surface changes to the TCBZ-resistant isolate than with each drug on its own, with greater swelling and blebbing of the tegument and even the loss of the apical plasma membrane in places. With the Cullompton isolate, there was limited potentiation of drug action in combination with KTZ, and only with TCBZ.SO. The results support the concept of altered drug metabolism within TCBZ-resistant isolates and indicate that this process may play a role in the development of drug resistance.

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Section: Discussionmentioning

confidence: 98%

Enhancement of the drug susceptibility of a triclabendazole-resistant isolate of Fasciola hepatica using the metabolic inhibitor ketoconazole

et al. 2010

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“…17,23,24 Also, a few studies have shown that the metabolism of quinine through the CYP 3A4 pathway was inhibited in vivo by CYP 3A4 inhibitors such as ritonavir and ketoconazole. [25][26][27] Therefore, there is a possibility of drug-drug interactions, especially at metabolic pathways if quinine and ciprofloxacin are concurrently administered. However, there is sparse information regarding such interaction between quinine and ciprofloxacin, and there are no published data to describe the nature and the magnitude of in vivo metabolic drug-drug interaction between the 2 drugs.…”

Section: Discussionmentioning

confidence: 99%

Alteration of the Disposition of Quinine in Healthy Volunteers After Concurrent Ciprofloxacin Administration

Adegbola

Soyinka

Adeagbo³

et al. 2016

American Journal of Therapeutics

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This study evaluated the effects of concurrent ciprofloxacin administration on the disposition of quinine in healthy volunteers. Quinine (600-mg single dose) was administered either alone or with the 11th dose of ciprofloxacin (500 mg every 12 hours for 7 days) to 15 healthy volunteers in a crossover fashion. Blood samples collected at predetermined time intervals were analyzed for quinine and its major metabolite, 3-hydroxquinine, using a validated high-performance liquid chromatographic method. Administration of quinine plus ciprofloxacin resulted in significant increases (P < 0.05) in the total area under the concentration-time curve, maximum plasma concentration (Cmax), and terminal elimination half-life (T1/2b) of quinine compared with values with quinine dosing alone (AUC: 27.93 ± 8.04 vs. 41.62 ± 13.98 h·mg/L; Cmax: 1.37 ± 0.24 vs. 1.64 ± 0.38 mg/L; T1/2b: 16.28 ± 2.66 vs. 21.43 ± 3.22 hours), whereas the oral plasma clearance markedly decreased (23.17 ± 6.49 vs. 16.00 ± 5.27 L/h). In the presence of ciprofloxacin, there was a pronounced decrease in the ratio of AUC (metabolite)/AUC (unchanged drug) and highly significant decreases in Cmax and AUC of the metabolite (P < 0.05). Ciprofloxacin may increase the adverse effects of concomitantly administered quinine, which can have serious consequences on the patient. Thus, a downward dosage adjustment of quinine seems to be necessary when concurrently administered with ciprofloxacin.

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“…Furthermore, it is used in WHO-recommended artemisinin combination therapy with artesunate (31). Mefloquine is mainly metabolized by CYP3A4, as was shown by coincubation/coadministration with the isozyme-specific inhibitor ketoconazole and the CYP3A4 inducer rifampin, both in human hepatocytes in vitro and human volunteers in vivo (24,32,33). The pharmacologically inactive carboxymefloquine (34) is regarded as the major metabolite (35).…”

Section: Discussionmentioning

confidence: 99%

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

Piedade

Traub

Bitter

et al. 2015

Antimicrob Agents Chemother

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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...

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Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteers

Cited by 49 publications

References 19 publications

Enhancement of the drug susceptibility of a triclabendazole-resistant isolate of Fasciola hepatica using the metabolic inhibitor ketoconazole

Enhancement of the drug susceptibility of a triclabendazole-resistant isolate of Fasciola hepatica using the metabolic inhibitor ketoconazole

Alteration of the Disposition of Quinine in Healthy Volunteers After Concurrent Ciprofloxacin Administration

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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