title: Pharmacokinetics of the fasciocidal drug candidates MT04 and OZ78 in uninfected rats and in vitro pharmacodynamic studies.
abstract: OZ78 and MT04 are promising drug candidates against fascioliasis (fasciolosis). We determined basic pharmacokinetic (PK) parameters of OZ78 and MT04 in uninfected rats. Rats were treated with single oral doses of 50 mg/kg OZ78 or MT04. Blood samples were withdrawn at selected time points post treatment and the plasma concentrations were quantified by a validated liquid chromatography/mass spectrometry (LC/MS) method. The LC/MS method for MT04 and OZ78, initially developed for sheep plasma analysis, was adapted for rat plasma. In vitro pharmacodynamic studies with Fasciola hepatica incubated in solutions of either test agent complemented our work. The adapted and validated method was precise and accurate to measure OZ78 and MT04 in rat plasma. Accuracies for MT04 ranged from 87.9% to 104.7% with precisions not exceeding 14.3%. Precisions for OZ78 were lower than 9.8% and accuracies were between 88.4% and 105.3%. Following oral administration, maximum plasma concentrations (C max) of MT04 and OZ78 were 49.8 and 70.1 μg/ml after 2.7 h and 1.6 h, respectively (p > 0.05). The estimated area under the plasma time curves (AUCs) were comparable for MT04 and OZ78. Mean elimination half-lives (t1/2) of MT04 and OZ78 covered a range from 1 to 7 h. In vitro studies demonstrated that the fasciocidal activity of MT04 and OZ78 was dependent on the incubation-time, with exposure of flukes for 24 h to the drugs not being sufficient to kill the worms. In conclusion, differences in PK parameters of MT04 and OZ78 were observed in rats. However, further studies (e.g. in infected rats) are necessary to characterize these drugs in greater detail.
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland ; University of Basel, P.O. Box, CH-4003 Basel, Switzerland.
authors.forename: Carla
authors.initials: C
authors.lastname: Kirchhofer
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland ; University of Basel, P.O. Box, CH-4003 Basel, Switzerland.
authors.forename: Mireille
authors.initials: M
authors.lastname: Vargas
authors.affiliation: Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Huwyler
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland ; University of Basel, P.O. Box, CH-4003 Basel, Switzerland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keiser
keywords: Fascioliasis; MT04; OZ78; Pharmacokinetics