Influence of verapamil on the pharmacokinetics of the antiparasitic drugs ivermectin and moxidectin in sheep

Abstract

P-Glycoprotein (P-GP) is a transport protein that participates in the mechanism of active secretion of different molecules from the bloodstream to the gastrointestinal tract. The aim of the current work was to evaluate the effect of verapamil, a P-GP substrate, on the pharmacokinetic behaviour of the anthelmintics ivermectin and moxidectin in sheep. Thirty-two sheep were divided into four groups and treated orally with either ivermectin or moxidectin alone (200 micro g/kg) or co-administered with verapamil at 3 mg/kg (three times at 12 h intervals). Blood samples were collected over 30 days post-treatment and plasma was analysed to determine ivermectin and moxidectin concentrations by HPLC. The ivermectin peak concentration was significantly higher ( P=0.048) after ivermectin plus verapamil, compared with the ivermectin alone treatment. Ivermectin plasma availability was significantly higher following co-administration ( P=0.022). Verapamil had no effect on the kinetics of moxidectin. The significant alteration in the plasma disposition of ivermectin in sheep induced by verapamil, possibly due to interference with a P-GP-mediated elimination mechanism, may have an important impact on efficacy against resistant- or rate-limiting-parasites and on the persistency of its antiparasitic activity.

Modulation of the P-Glycoprotein-Mediated Intestinal Secretion of Ivermectin: In Vitro and in Vivo Assessments

“…Differential P-gp transport properties between IVM and other closely related macrocyclic lactone compounds (moxidectin, eprinomectin, etc.) have been suggested previously Molento et al, 2004). Thus, the application of the everted sac technique described here may result in a straightforward in vitro method to further characterize the comparative intestinal transport of the different IVM-related compounds as well as the impact of its modulation, which may have a remarkable relevance in antiparasitic therapy.…”

Alternativas para o controle de nematoides gastrintestinais de pequenos ruminantes

“…O aumento da atividade anti-helmíntica de ivermectina e de moxidectina associada ao verapamil foi observado em um modelo experimental utilizando cobaias (Meriones unguiculatus) experimentalmente infectadas com larvas de H. contortus resistentes. Além do efeito direto na reversão à resistência anti-helmíntica, a inibição da P-gp por drogas moduladoras aumenta a biodisponibilidade do anti-helmíntico, aumentando, consequentemente, a eficácia contra nematoides resistentes (MolEnTo et al, 2004b O objetivo do método FAMACHA é identificar animais anêmicos que não são aptos a tolerar a hemoncose (doença causada pelo H. contortus, o verme que se alimenta de sangue e que por isso pode causar anemia que, dependendo da gravidade, pode levar o animal à morte). Aqueles que se encontram com os graus 3, 4 ou 5 receberão o vermífugo, permitindo que o restante do rebanho permaneça sem tratamento.…”

Weak phenotypic reversion of ivermectin resistance in a field resistant isolate of Haemonchus contortus by verapamil

“…Along with the direct action of resistance reversion, VRP can significantly increase some pharmacokinetic parameters (AUC and Cmax) of co-administrated IVM in sheep, probably due to liver and intestinal Pgp inhibition, thereby reducing biliary excretion and increasing the intestinal absorption of IVM (Molento et al 2004). Lespine et al (2008) pointed that the study of Pgp modulators should follow the following steps: selection of the drug, evaluation of the ability of this drug to modulate Pgp action in cells, pharmacokinetic studies in the host, in vitro tests with resistant parasites and in vivo coadministration of anthelmintic and Pgp modulator on experimentally infected hosts.…”

“…All the studies on Pgp modulators in ruminants (Molento et al 2004, Lifschitz et al 2010a used the drug diluted in saline solution. The use of a formulation containing the association of a Pgp modulator and ivermectin in an oil-based vehicle could reduce the rate of absorption from the injection site, resulting in prolonged residence time and longer effect of the drug on Pgp modulation.…”