caa a22 4500 445340894 CHVBK 20180317142812.0 cr unu---uuuuu 170323e20111001xx s 000 0 eng 10.1007/s00436-011-2304-9 doi (NATIONALLICENCE)springer-10.1007/s00436-011-2304-9 Inhibition of triclabendazole metabolism in vitro by ketoconazole increases disruption to the tegument of a triclabendazole-resistant isolate of Fasciola hepatica [Elektronische Daten] [C. Devine, G. Brennan, C. Lanusse, L. Alvarez, A. Trudgett, E. Hoey, I. Fairweather] A study has been carried out to investigate whether the action of triclabendazole (TCBZ) against Fasciola hepatica is altered by inhibition of drug metabolism. The cytochrome P450 (CYP 450) enzyme pathway was inhibited using ketoconazole (KTZ) to see whether a TCBZ-resistant isolate could be made more sensitive to TCBZ action. The Oberon TCBZ-resistant and Cullompton TCBZ-susceptible isolates were used for these experiments. The CYP 450 system was inhibited by a 2-h pre-incubation in ketoconazole (40μM), then incubated for a further 22h in NCTC medium containing either KTZ, KTZ + nicotinamide adenine dinucleotide phosphate (NADPH) (1nM), KTZ + NADPH + TCBZ (15μg/ml), or KTZ + NADPH + triclabendazole sulphoxide (TCBZ.SO; 15μg/ml). Changes to fluke ultrastructure following drug treatment and metabolic inhibition were assessed using transmission electron microscopy. After treatment with either TCBZ or TCBZ.SO on their own, there was greater disruption to the TCBZ-susceptible than TCBZ-resistant isolate. However, co-incubation with KTZ + TCBZ, but more particularly KTZ + TCBZ.SO, led to more severe changes to the TCBZ-resistant isolate than with each drug on its own: in the syncytium, for example, there was severe swelling of the basal infolds and their associated mucopolysaccharide masses, accompanied by an accumulation of secretory bodies just below the apex. Golgi complexes were greatly reduced or absent in the tegumental cells and the synthesis, production, and transport of secretory bodies were badly disrupted. With the TCBZ-susceptible Cullompton isolate, there was limited potentiation of drug action. The results support the concept of altered drug metabolism in TCBZ-resistant flukes and this process may play a role in the development of drug resistance. Springer-Verlag, 2011 Devine C. Parasite Therapeutics Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BT9 7BL, Belfast, UK aut Brennan G. Parasite Therapeutics Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BT9 7BL, Belfast, UK aut Lanusse C. Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario (UNCPBA), 7000, Tandil, Argentina aut Alvarez L. Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario (UNCPBA), 7000, Tandil, Argentina aut Trudgett A. Parasite Therapeutics Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BT9 7BL, Belfast, UK aut Hoey E. Parasite Therapeutics Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BT9 7BL, Belfast, UK aut Fairweather I. Parasite Therapeutics Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BT9 7BL, Belfast, UK aut Parasitology Research Springer-Verlag 109/4(2011-10-01), 981-995 0932-0113 109:4<981 2011 109 436 https://doi.org/10.1007/s00436-011-2304-9 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00436-011-2304-9 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Devine C. Parasite Therapeutics Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BT9 7BL, Belfast, UK aut NATIONALLICENCE 700 1- Brennan G. Parasite Therapeutics Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BT9 7BL, Belfast, UK aut NATIONALLICENCE 700 1- Lanusse C. Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario (UNCPBA), 7000, Tandil, Argentina aut NATIONALLICENCE 700 1- Alvarez L. Laboratorio de Farmacología, Departamento de Fisiopatología, Facultad de Ciencias Veterinarias, Universidad Nacional del Centro de la Provincia de Buenos Aires, Campus Universitario (UNCPBA), 7000, Tandil, Argentina aut NATIONALLICENCE 700 1- Trudgett A. Parasite Therapeutics Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BT9 7BL, Belfast, UK aut NATIONALLICENCE 700 1- Hoey E. Parasite Therapeutics Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BT9 7BL, Belfast, UK aut NATIONALLICENCE 700 1- Fairweather I. Parasite Therapeutics Group, School of Biological Sciences, Medical Biology Centre, The Queen's University of Belfast, 97 Lisburn Road, BT9 7BL, Belfast, UK aut NATIONALLICENCE 773 0- Parasitology Research Springer-Verlag 109/4(2011-10-01), 981-995 0932-0113 109:4<981 2011 109 436 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer