Pharmacokinetics of zonisamide and drug interaction with phenobarbital in dogs

Abstract

The purposes of the present study were to elucidate the pharmacokinetics of zonisamide, determine the presence of a drug interaction with phenobarbital, and evaluate how long any interaction lasted after discontinuation of phenobarbital in dogs. Five dogs received zonisamide (5 mg/kg, p.o. and i.v.) before and during repeated oral administration of phenobarbital (5 mg/kg, bid, for 30-35 days). Zonisamide (5 mg/kg, p.o.) was also administered 8, 10, and 12 weeks after discontinuation of phenobarbital. Blood was sampled until 24 h after each zonisamide administration and serum concentrations of zonisamide were determined. Repeated phenobarbital decreased the maximum serum concentration, area under the serum concentration vs. time curve, apparent elimination half-life, and bioavailability of zonisamide. Total clearance increased. Time to maximum serum concentration and volume distribution were not changed. The maximum serum concentration and area under the serum concentration vs. time curve of zonisamide continued to be low until 10 weeks after the discontinuation of phenobarbital. They were restored to the same serum concentration as before phenobarbital administration 12 weeks after the discontinuation of phenobarbital. These data suggested that repeated administration of a clinical dose of phenobarbital enhanced the clearance of zonisamide and the enhanced clearance lasted at least 10 weeks after the discontinuation of phenobarbital. Caution may be necessary when zonisamide is given with phenobarbital and when antiepileptic therapy is changed from phenobarbital to zonisamide.

Status epilepticus in dogs and cats, part 2: treatment, monitoring, and prognosis

“…In a 2004 study of dogs with idiopathic epilepsy, 58% of dogs had decreased seizure frequency when zonisamide was added to phenobarbital and potassium bromide . Of interest is that phenobarbital may increase the clearance of zonisamide for up to 10 weeks …”

Steady-state pharmacokinetics of zonisamide in plasma, whole blood, and erythrocytes in dogs

“…, 1996). Zonisamide, on the other hand, has a long half‐life (over 15 h) (Orito et al. , 2008), a wide range of effective plasma concentrations, and shows effectiveness in a model of experimentally induced seizures in dogs (Masuda et al.…”

“…These data are indispensable when one attempts to determine a clinical dosage regimen and/or predict side effects (Matsumoto et al. , 1983; Orito et al. , 2008).…”

Pharmacovigilance in veterinary medicine in Chile: a pilot study

“…Of special interest are drugs approved for commercialization, mainly because safety data is based on studies performed in animals whose exposure would not normally correspond to that of animals treated in clinical practice. For instance, concomitant administration of drugs may be the source of drug interactions leading to ADRs (Amatori et al, 2004;Kuroha et al, 2004;Orito et al, 2008;Yap et al, 2008).…”