Evaluation of the interaction between ivermectin and albendazole following their combined use in lambs

Abstract

Mixtures of drugs from different chemical families have been proposed as a valid strategy to delay the development of anthelmintic resistance. The current work summarizes the outcome of the evaluation of the plasma disposition kinetics of albendazole (ABZ) and ivermectin (IVM) administered either alone or co-administered to lambs infected with gastrointestinal (GI) nematodes resistant to both anthelmintic molecules. Thirty six (36) Corriedale lambs naturally infected with multiple resistant GI nematodes were allocated into six treatment groups: (a) ABZ intravenous (ABZ(IV)); (b) IVM(IV); (c) ABZ(IV) + IVM(IV); (d) ABZ intraruminal (IR); (e) IVM subcutaneous (SC) and (f) ABZ(IR) + IVM(SC). Plasma samples were collected over 15 days post-treatment and analysed by HPLC. The estimated pharmacokinetic (PK) parameters were statistically compared using parametric and non-parametric statistical tests. The presence of IVM did not affect the plasma disposition kinetics of ABZ and its metabolites after the i.v. administration. However, the ABZ sulphoxide (ABZSO) area under the concentration vs. time curve (AUC) was significantly lower (P < 0.01) after the intraruminal (i.r.) administration of ABZ alone compared to that obtained for the combined treatment with IVM [subcutaneous (s.c.) injection]. The IVM plasma AUC obtained after its i.v. co-administration with ABZ was 88% higher (P < 0.05) compared to the treatment with IVM alone. Any marked difference on IVM PK parameters was observed between the treatments ABZ + IVM and IVM alone injected subcutaneously. The data obtained here indicate that the co-administration of ABZ and IVM does not induce an adverse kinetic interaction. This type of pharmacology-based evaluation of drug interactions is becoming highly relevant as drug combinations are now widely used as an alternative to control resistant helminth parasites in livestock.

Unchanged triclabendazole kinetics after co-administration with ivermectin and methimazole: failure of its therapeutic activity against triclabendazole-resistant liver flukes

“…Increased albendazole sulphoxide plasma concentrations in lambs after co-administration of albendazole (intraruminally, i.r.) with IVM (subcutaneously, s.c.), was previously reported [16]. Similarly, after the co-administration to sheep of IVM and TCBZ by the intravenous (i.v.)…”

Flubendazole and ivermectin in vitro combination therapy produces a marked effect on Echinococcus granulosus protoscoleces and metacestodes

“…In fact, pharmacokinetic interaction between ABZ and IVM has been recently reported in sheep (Alvarez et al 2008). Although it was unclear at which level ABZ/metabolites and IVM interact, two possible explanations were as follows: (1) IVM-induced inhibition of ABZ metabolism or (2) drug-to-drug interaction via drug efflux transportersmediated mechanisms.…”

Natural Allelic Variants of Bovine ATP-Binding Cassette Transporter ABCG2: Increased Activity of the Ser581 Variant and Development of Tools for the Discovery of New ABCG2 Inhibitors

“…In vivo pharmacokinetic interactions of macrocyclic lactones with ABCG2 substrates are also expected. In fact, ivermectin competition on elimination of the ABCG2 substrate albendazolesulfoxide may explain the enhanced drug concentration observed in lambs after coadministration of ivermectin and albendazole (Merino et al, 2003;Alvarez et al, 2008).…”