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Evaluation of the pharmacokinetic profile of artesunate, artemether and their metabolites in sheep naturally infected with Fasciola hepatica

Duthaler, U. and Huwyler, J. and Rinaldi, L. and Cringoli, G. and Keiser, J.. (2012) Evaluation of the pharmacokinetic profile of artesunate, artemether and their metabolites in sheep naturally infected with Fasciola hepatica. Veterinary parasitology, Vol. 186, H. 3-4. pp. 270-280.

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Official URL: http://edoc.unibas.ch/dok/A6043716

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Abstract

The pharmacokinetic (PK) parameters of artesunate, artemether and their metabolites dihydroartemisinin (DHA) and dihydroartemisinin-glucuronide (DHA-glucuronide) were determined in sheep naturally infected with Fasciola hepatica. Sheep were treated either with artesunate (intramuscular (i.m.): 40 and 60mg/kg) or artemether (i.m.: 40 and 160mg/kg; oral: 80mg/kg). Blood samples were withdrawn at selected time points post treatment and the artemisinins were quantified in plasma by liquid chromatography and tandem mass spectrometry (LC-MS/MS). The in vitro effect of the metabolites against F. hepatica was investigated using a phenotype-based assay and scanning electron microscopy (SEM). Following artesunate applications (40 and 60mg/kg), comparable C(max) (maximal plasma concentration) and AUCs (area under the plasma concentration-time curve) were observed for artesunate (C(max): 8.4x10(3) and 9.4x10(3)ng/ml; AUC: 6.9x10(5) and 9.7x10(5)ngmin/ml), DHA (C(max): both 2.4x10(3)ng/ml; AUC: 3.7x10(5) and 5.0x10(5)ngmin/ml), and DHA-glucuronide (C(max): 1.7x10(4) and 1.6x10(4)ng/ml; AUC: 2.6x10(6) and 3.3x10(6)ngmin/ml). Mean elimination half-lifes (t(1/2)) of artesunate, DHA and DHA-glucuronide ranged between 58 and 63min, 94 and 113min, and 89 and 98min, respectively. The i.m. oil-based drug formulation liberated artemether slowly and constant levels of artemether and its metabolites were observed during the entire sampling period (24h). The AUCs of all analytes were significantly higher for the i.m. 160mg/kg dose compared to i.m. 40 and oral 80mg/kg doses (P=0.018). Mean C(max) of artemether (2126 and 426ng/ml) and DHA-glucuronide (3477 and 1587ng/ml) were higher following oral compared to i.m. (160mg/kg) treatments (P<0.068), whereas C(max) of DHA was significantly higher following i.m. applications (P=0.0062). DHA rapidly reduced the viability of F. hepatica in vitro, whereas DHA-glucuronide showed no activity. SEM observations revealed only minor and focal tegumental alterations in few of the DHA treated worms. The calculated PK parameters reflect the anthelmintic activity of artesunate and artemether following different routes of application and will aid in the design of future studies with these drugs.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmazeutische Technologie (Huwyler)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Helminth Drug Development (Keiser)
UniBasel Contributors:Huwyler, Jörg and Duthaler, Urs and Keiser, Jennifer
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Elsevier
ISSN:0304-4017
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:19 Jul 2013 07:41
Deposited On:04 Jan 2013 08:35

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