Absorption and Distribution of Toltrazuril and Toltrazuril Sulfone in Plasma, Intestinal Tissues and Content of Piglets after Oral or Intramuscular Administration

Abstract

Piglet coccidiosis due to Cystoisospora suis is a major cause of diarrhea and poor growth worldwide. It can effectively be controlled by application of toltrazuril (TZ), and oral formulations have been licensed for many years. Recently, the first parenteral formulation containing TZ in combination with iron (gleptoferron) was registered in the EU for the prevention of coccidiosis and iron deficiency anemia, conditions in suckling piglets requiring routine preventive measures. This study evaluated the absorption and distribution of TZ and its main metabolite, toltrazuril sulfone (TZ-SO2), in blood and intestinal tissues after single oral (20 mg/kg) or single intramuscular (45 mg/piglet) application of TZ. Fifty-six piglets were randomly allocated to the two treatment groups. Animals were sacrificed 1-, 5-, 13-, and 24-days post-treatment and TZ and TZ-SO2 levels were determined in blood, jejunal tissue, ileal tissue, and mixed jejunal and ileal content (IC) by high performance liquid chromatography (HPLC). Intramuscular application resulted in significantly higher and more sustained concentrations of both compounds in plasma, intestinal tissue, and IC. Higher concentrations after oral dosing were only observed one day after application of TZ in jejunum and IC. Toltrazuril was quickly metabolized to TZ-SO2 with maximum concentrations on day 13 for both applications. Remarkably, TZ and TZ-SO2 accumulated in the jejunum, the primary predilection site of C. suis, independently of the administration route, which is key to their antiparasitic effect.

Pharmacokinetics, bioavailability, and excretion of ponazuril in piglets

“…In addition, Karembe et al reported the disposition kinetics of toltrazuril and ponazuril in plasma and the intestinal tissues after oral and intramuscular application of toltrazuril in piglets. This study observed that after the metabolism of toltrazuril to ponazuril, both showed significant and sustained concentrations in the jejunal tissue where C. suis mainly colonize, as well as in the intestinal contents ( 49 ). We have not yet obtained sufficient data to demonstrate the mechanisms involved in the higher and more sustained plasma, tissue, and fecal concentrations.…”

Pharmacokinetics of toltrazuril and its metabolite, toltrazuril sulfone, in suckling piglets following oral and intramuscular administrations

“…administration was higher than the p.o. administration (Karembe et al, 2021). In the current study, we measured the central pharmacokinetics and tissue (muscle and liver in addition to jejunum) distributions of TZR and TZR‐SO 2 after p.o.…”

“…Extraction procedures were based on previously published methods (Karembe et al, 2021; Soliman, 2015) with slight modifications. Briefly, frozen serum samples were thawed at room temperature, then 400 μL of ethyl acetate was added to 200 μL of the serum sample and vortexed for 1 min.…”

“…The HPLC method was slightly modified from the previously published methods (Karembe et al, 2021; Soliman, 2015). The TZR concentrations were analyzed using a Waters model 1525 HPLC system equipped with a model 2489 UV–visible detector (Waters).…”

“…and intramuscular (i.m.) administrations of TZR (Karembe et al, 2021). The result indicated that regardless of administration routes, TZR and TZR‐SO 2 accumulated in the jejunum where C. suis mainly resides.…”