P-glycoprotein modulation modifies ivermectin pharmacokinetics and its efficacy against resistant nematodes in lambs

LIFSCHITZ, A.; ENTROCASSO, C.; ALVAREZ, L.; LLOBERAS, M.; BALLENT, M.; MANAZZA, J.; VIRKEL, G.; BORDA, B.; LANUSSE, C.

Leipzig, Alemania

Congreso; 11th International Congress of the European Association for Veterinary Pharmacology and Toxicology; 2009

EAVPT

Introduction: P-glycoprotein (P-gp) is a transmembrane protein which is able to pump a broad range of unrelated compounds out of the cell by an ATP-dependent process. P-gp is physiologically expressed in a number of tissues including liver, blood-brain barrier and intestine (1). Ivermectin (IVM) is a macrocyclic lactone (ML) compound used as a broad-spectrum anthelmintic in veterinary medicine. The involvement of P-gp on IVM disposition kinetics has been demonstrated. P-gp is involved on IVM intestinal secretion in rats (2, 3). Enhanced moxidectin and IVM plasma availabilities were observed after their in vivo co-administration with loperamide (LPM) in different animal species (4, 5). It has also been reported that ML treatments select for a constitutive or inducible P-gp over expression in worms (6). The work reported here aimed to study the effects of LPM, a P-gp modulating agent, on IVM pharmacokinetics and efficacy against resistant nematodes in lambs.   Material and Methods: Eighteen (18) Corriedale lambs naturally infected with gastrointestinal nematodes (faecal nematode egg counts ranging from 2520 to 6960) were assigned into three (3) experimental groups. Animal’s management was in agreement with internationally accepted welfare guidelines. Group A (n= 6) remained as untreated control. Lambs in Groups B and C received IVM (subcutaneously at 0.2 mg/kg) either alone or co-administered with LPM (0.2 mg/kg, twice every 12 h).  Blood samples were collected between 0 and 14 days post-treatment and IVM plasma concentrations were determined by HPLC with fluorescent detection (Pharmacokinetic trial). Faecal individual samples were collected from all animals pre-treatment (day-1) and at 14 days post-treatment to estimate the epg counts. Additionally, at day 14 post-treatment, the experimental lambs were sacrificed and direct adult gastrointestinal nematode counts were performed following recommended parasitological guidelines. The pattern of drug activity was estimated by the faecal egg count reduction test (FECRT) and adult nematode counts (Efficacy trial). Results: The presence of the P-gp modulating agent (LPM) affected the IVM plasma disposition in lambs. LPM enhanced the IVM plasma availability (47 %) (P< 0.05) and prolonged its elimination half-life (61 %) (P< 0.05) in co-administered lambs. The overall anthelmintic efficacy observed confirms the presence of nematodes resistant to IVM. The epg counts in lambs treated with IVM+LPM were significantly lower (P< 0.05) compared to those obtained in the untreated control and IVM alone treated animals. The overall FECRT values increased from 79 % to 96 % in the presence of LPM. Similarly, the adult IVM nematodicidal activity was enhanced after its co-administration with LPM. The efficacy against Trichostrongylus colubriformis increased from 77.9 % (IVM alone) to 96.3 % (IVM +LPM). A similar trend was observed for Nematodirus spp.   Conclusions: LPM affects the disposition kinetics and enhances IVM anthelmintic efficacy against resistant nematodes.  LPM modulates the P-gp–mediated intestinal and hepatic excretion of IVM, which may account for the observed kinetic modifications. Additionally, LPM may interact with the P-gp efflux transport overexpressed in resistant nematodes, increasing worm exposure to IVM. The clinical relevance of this pharmacokinetic/pharmacodynamic interaction is under further analysis in our laboratory.