Pharmacokinetics of single-dose rectal zonisamide administration in normal dogs

Abstract

Background: Few medications are available for parental administration to animals with seizures. Rectal administration of medications is often used if the animal cannot be administered oral medications.

Hypothesis/objectives: To determine the pharmacokinetic differences in zonisamide when administered rectally in either of 2 vehicles and p.o. to dogs.

Animals: Eight healthy research dogs.

Methods: Randomized cross-over design. Zonisamide, 10 mg/kg, was administered rectally in polyethylene glycol (PEG-R), rectally in water (H2O-R), and as an oral capsule. Plasma zonisamide concentrations were measured until 72 hours after administration. Zonisamide was quantitated by HPLC and plasma concentration versus time curve data was analyzed by using noncompartmental modeling.

Results: Mean maximum plasma zonisamide concentrations (μg/mL) were significantly higher after oral administration (11.56 ± 4.04) compared to H2O-R (5.00 ± 1.83) (P = .004). Disappearance half-life (hours) and mean time to maximum concentration (hours) were not significantly different between methods of administration. Mean relative bioavailability of PEG-R (85 ± 69%) was significantly higher than that of H2O-R (53 ± 37%) (P = .039). Dogs tolerated all dosing forms with no evidence of adverse effects.

Conclusions and clinical importance: The vehicle in which zonisamide is dissolved influences rectal bioavailability, with PEG preferred to H2O-R. Because of the prolonged time to maximum concentration, rectal administration of zonisamide should not be used to treat status epilepticus in dogs. A dose higher than what was used in this study might be necessary, if currently recommended minimum therapeutic concentrations (10 μg/mL) are to be achieved with a single-dose administration.

Keywords: Bioavailability; Epilepsy; Polyethylene glycol; Seizure; Status epilepticus.

Figure 1

Mean plasma zonisamide concentrations for Oral, PEG‐R, and H₂O‐R routes.