Title:Macrocyclic Lactones and Cellular Transport-Related Drug Interactions: A Perspective from In Vitro Assays to Nematode Control in the Field
Volume: 13
Issue: 6
Author(s): A. Lifschitz, M. Ballent and C. Lanusse
Affiliation:
Keywords:
ABC transporters, drug combinations, drug-drug interactions, macrocyclic lactones
Abstract: Macrocyclic lactones (MLs) are antiparasitic drugs used against endo-ectoparasites. Regarding the wide use of
MLs in different species, it is likely that drug-drug interactions may occur after their co-administration with other compounds.
A new paradigm was introduced in the study of the pharmacology of MLs during the last years since the interactions
of MLs with ATP-binding cassete (ABC) transporters have been described. The current review article gives an update
on the available information concerning drug-drug interactions involving the MLs. The basis of the methodological
approaches used to evaluate transport interactions, and the impact of the pharmacology-based modulation of drug transport
on the MLs disposition kinetics and clinical efficacy, are discussed in an integrated manner. A different number of in
vitro and ex vivo methods have been reported to study the characterization of the interactions between MLs and ABC
transporters. The production of the ABC transporters knockout mice has provided valuable in vivo tools to study this type
of drug-drug interaction. In vivo trials performed in different species corroborated the effects of ABC transporter modulators
on the pharmacokinetics behaviour of MLs. Important pharmacokinetic changes on plasma disposition of MLs have
been observed when these compounds are co-administered with P-glycoprotein modulators. The modulation of the activity
of P-glycoprotein was evaluated as a strategy not only to increase the systemic availability of MLs but also to improve
their clinical efficacy. The understanding of the MLs interactions may supply relevant information to optimize their use in
veterinary and human therapeutics.
