INVESTIGADORES
LIFSCHITZ Adrian Luis
artículos
Título:
Cattle nematodes resistant to macrocyclic lactones: comparative effects of P-glycoprotein modulation on the efficacy and disposition kinetics of ivermectin and moxidectin.
Autor/es:
LIFSCHITZ A,; SUAREZ VH,; SALLOVITZ J,; CRISTEL SL,; IMPERIALE F,; AHOUSSOU S,; SCHIAVI C,; LANUSSE C.
Revista:
EXPERIMENTAL PARASITOLOGY
Editorial:
ACADEMIC PRESS INC ELSEVIER SCIENCE
Referencias:
Año: 2010 vol. 125 p. 172 - 178
ISSN:
0014-4894
Resumen:
The role of the drug efflux pump, known as P-glycoprotein, in the pharmacokinetic disposition (host) and
resistance mechanisms (target parasites) of the macrocyclic lactone (ML) antiparasitic compounds has
been demonstrated. To achieve a deeper comprehension on the relationship between their pharmacokinetic
and pharmacodynamic behaviors, the aim of the current work was to assess the comparative effect
of loperamide, a well-established P-glycoprotein modulator, on the ivermectin and moxidectin disposition
kinetics and efficacy against resistant nematodes in cattle. Fifty (50) Aberdeen Angus male calves
were divided into five (5) experimental groups. Group A remained as an untreated control. Animals in
the other experimental Groups received ivermectin (Group B) and moxidectin (Group C) (200 lg/kg, subcutaneuosly)
given alone or co-administered with loperamide (0.4 mg/kg, three times every 24 h)
(Groups D and E). Blood samples were collected over 30 days post-treatment and drug plasma concentrations
were measured by HPLC with fluorescence detection. Estimation of the anthelmintic efficacy for the
different drug treatments was performed by the faecal egg count reduction test (FECRT). Nematode larvae
were identified by pooled faecal cultures for each experimental group. Cooperia spp. and Ostertagia spp.
were the largely predominant nematode larvae in pre-treatment cultures. A low nematodicidal efficacy
(measured by the FECRT) was observed for both ivermectin (23%) and moxidectin (69%) in cattle, which
agrees with a high degree of resistance to both molecules. Cooperia spp. was the most abundant nematode
species recovered after the different drug treatments. The egg output reduction values increased
from 23% to 50% (ivermectin) and from 69% to 87% (moxidectin) following their co-administration with
loperamide. Enhanced systemic concentrations and an altered disposition of both ML in cattle, which correlates
with a tendency to increased anthelmintic efficacy, were observed in the presence of loperamide.
Overall, the in vivo modulation of P-glycoprotein activity modified the kinetic behavior and improved the
efficacy of the ML against resistant nematodes in cattle. The work provides further evidence on the high
degree of resistance to ML in cattle nematodes and, shows for the first time under field conditions, that
modulation of P-glycoprotein may be a valid pharmacological approach to improve the activity and
extend the lifespan of these antiparasitic molecules.