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Pharmacokinetics of the antischistosomal lead OZ418 in uninfected mice determined by LC-MS/MS

Leonidova, Anna and Vargas, Mireille and Huwyler, Jörg and Keiser, Jennifer. (2016) Pharmacokinetics of the antischistosomal lead OZ418 in uninfected mice determined by LC-MS/MS. Antimicrobial agents and chemotherapy, 60 (12). pp. 7364-7371.

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Official URL: http://edoc.unibas.ch/54415/

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Abstract

One of the major neglected tropical diseases, schistosomiasis, is currently treated and controlled with a single drug, praziquantel. The quest for an alternative drug is fueled by the lack of activity of praziquantel against juvenile Schistosoma worms and the fear of emerging resistance. The synthetic ozonide OZ418 has shown high activity against Schistosoma mansoni, S. haematobium, and S. japonicum in vivo, but its drug disposition remains unknown. To bridge this gap, our study determined the basic pharmacokinetic (PK) parameters of a single oral dose (400 mg/kg of body weight) of OZ418 in uninfected mice. First, a simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify OZ418 concentrations in mouse plasma was successfully developed and validated according to U.S. FDA guidelines. This method proved to be selective, accurate (93 to 103%), precise (5 to 16%), and devoid of significant matrix effects (90 to 102%) and provided excellent recovery (101 to 102%). A median peak concentration of 190 (range, 185 to 231) μg/ml was reached at 2 h (2 to 3 h) posttreatment. A naive pooled noncompartmental PK analysis estimated a mean area under the plasma concentration-versus-time curve (AUC) of 9,303 μg h/ml (7,039.2 to 11,908.5 μg h/ml) and a half-life of 38.7 h (20 to 64.6 h). Thus, the OZ418 level in plasma remained well above its in vitro 50% inhibitory concentrations (IC50s) of 27.4 μg/ml (adult S. mansoni worms at 72 h) for at least 75 h. Consistently, OZ418 degraded little in plasma at 37°C (<20% in 121 h) and weakly inhibited cytochrome P450 (CYP450) metabolism (IC50 of 37 to 144 μM). Our results provide a first insight into the disposition of OZ418, paving the way for further studies of its biological fate and effect.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Helminth Drug Development (Keiser)
UniBasel Contributors:Keiser, Jennifer and Vargas, Mireille
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Microbiology
ISSN:0066-4804
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:20 Apr 2017 13:23
Deposited On:20 Apr 2017 13:23

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