Títol:
|
Cytochrome P450/ABC transporter inhibition simultaneously
enhances ivermectin pharmacokinetics in the mammal host and
pharmacodynamics in Anopheles gambiae
|
Autor/a:
|
Chaccour, Carlos; Hammann, Felix; Alustiza, Marta; Castejon, Sandra; Tarimo, Brian B.; Abizanda, Gloria; Irigoyen Barrio, Ángel; Marti Soler, Helena; Moncada, Rafael; Bilbao, José Ignacio; Aldaz, Azucena; Maia, Marta; Pozo, José Luis Del
|
Abstract:
|
Mass administration of endectocides, drugs that kill
blood-feeding arthropods, has been proposed as a complementary
strategy to reduce malaria transmission. Ivermectin is one of
the leading candidates given its excellent safety profile. Here
we provide proof that the effect of ivermectin can be boosted at
two different levels by drugs inhibiting the cytochrome or ABC
transporter in the mammal host and the target mosquitoes. Using
a mini-pig model, we show that drug-mediated cytochrome P450/ABC
transporter inhibition results in a 3-fold increase in the time
ivermectin remains above mosquito-killing concentrations. In
contrast, P450/ABC transporter induction with rifampicin
markedly impaired ivermectin absorption. The same
ketoconazole-mediated cytochrome/ABC transporter inhibition also
occurs outside the mammal host and enhances the mortality of
Anopheles gambiae. This was proven by using the samples from the
mini-pig experiments to conduct an ex-vivo synergistic bioassay
by membrane-feeding Anopheles mosquitoes. Inhibiting the same
cytochrome/xenobiotic pump complex in two different organisms to
simultaneously boost the pharmacokinetic and pharmacodynamic
activity of a drug is a novel concept that could be applied to
other systems. Although the lack of a dose-response effect in
the synergistic bioassay warrants further exploration, our study
may have broad implications for the control of parasitic and
vector-borne diseases. |
Matèries:
|
-Malària -Medicina tropical -Malaria -Tropical medicine |
Drets:
|
cc by (c) Chaccour et al. , 2017
http://creativecommons.org/licenses/by/4.0/ |
Tipus de document:
|
Article Article - Versió publicada |
Publicat per:
|
Nature Publishing Group
|
Compartir:
|
|