Cerebrospinal fluid and blood concentrations of toltrazuril 5% suspension in the horse after oral dosing.

Abstract: Toltrazuril 5% suspension (Baycox, Bayer Canada, Ontario, Canada) was administered to six adult horses followed by blood collection and assay to determine the concentration of toltrazuril and its principal metabolites, toltrazuril sulfone and toltrazuril sulfoxide. From this data, the maximum concentration (C(max)), elimination half-life (T 1/2), and mean residence times of the plasma were determined from standard pharmacokinetic formulas. After a single oral dose of 10 mg/kg body weight a rapid absorption was found, with a mean peak serum concentration of 11.17 mg/L at 18 hours. Elimination was prolonged, with a mean T 1/2 for elimination of 61.4 hours. In addition, toltrazuril was administered to nine horses, and blood serum and cerebrospinal fluid (CSF) concentrations of toltrazuril and its principal metabolites were determined. Horses were randomly assigned to one of three treatment groups and received either 2.5 mg/kg body weight (Group A), 5.0 mg/kg body weight (Group B), or 7.5 mg/kg body weight (Group C) orally, once daily, for 10 days. Jugular venous blood was collected routinely on treatment days 2, 6, and 10, and CSF was collected on treatment day 10. Assay of toltrazuril and its metabolites revealed a dose-dependent effect within both the blood and CSF compartments. Mean concentrations within the CSF after 10 days of treatment were 0.146 mg/L in Group A, 0.190 mg/L in Group B, and 0.386 mg/L in Group C. Toltrazuril sulfone was the primary metabolite after 10 days of treatment, with concentrations that ranged from 39% to 116% of the parent drug in individual animals. Toltrazuril sulfone was also the predominant metabolite in the serum at treatment day 10; however, it did not always exceed the concentration of toltrazuril sulfoxide in the serum on treatment day 2. In the serum, drug concentrations at treatment day 2 were variable in the low-dose group (Group A), ranging from 4.0 to 11.61 mg/L; less variable in the high-dose group (Group C), ranging from 9.9 to 10.46 mg/L; and intermediate in Group B. This study confirms that toltrazuril is absorbed in the horse after oral administration and reaches effective in vitro concentrations within the CSF of the horse after once-daily dosing of 5 or 7.5 mg/kg. Although these data suggest that toltrazuril may have clinical value in the treatment of equine protozoal myeloencephalitis, clinical efficacy remains to be confirmed using appropriate methods. Effective in vitro concentrations are known; however, therapeutic concentrations in vivo have not been established. Further research in this area is needed to determine various drug values in the CSF (e.g., half-life, C(max), time to reach steady state).