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Disposition and safety of zonisamide after intravenous and oral single dose and oral multiple dosing in normal hound dogs.

Author(s): Boothe DM, Perkins J

Affiliation(s): Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, AL 36849-5518, USA. boothdm@auburn.edu

Publication date & source: 2008-12, J Vet Pharmacol Ther., 31(6):544-53.

Publication type: Research Support, Non-U.S. Gov't

The purpose of this study was to determine an oral dosing regimen of zonisamide in healthy dogs such that therapeutic concentrations would be safely reached and maintained at steady-state. Adult hound dogs (n = 8) received a single IV (6.9) and an oral (PO) dose (10.3 mg/kg) using a randomized cross-over design. Zonisamide was then administered at 10.3 mg/kg PO every 12 h for 8 weeks. Zonisamide was quantitated in blood compartments or urine by HPLC and data were subjected to noncompartmental pharmacokinetic analysis. Comparisons were made among blood compartments (one-way anova; P </= 0.05). Differences among blood compartments occurred in all derived pharmacokinetic paramenters for each route of administration after single and multiple dosing. After single PO dosing, plasma C(max) was 14.4 +/- 2.3 mcg/mL and elimination half-life was 17.2 +/- 3.6 h. After IV dosing, volume of distribution was 1.1 +/- 0.25 L/kg, clearance was 58 +/- 11 mL/h/kg and elimination t(1/2) was 12.9 +/- 3.6 h. Oral bioavailability was 68 +/- 12%; fraction of unbound drug approximated 60%. At steady-state (4 days), differences occurred for for all parameters except C(max) and C(min.) Plasma C(max) at steady-state was 56 +/- 12 mcg/mL, with 10% fluctuation between C(max) and C(min.) Plasma t(1/2) (h) was 23.52 +/- 5.76 h. Clinical laboratory tests remained normal, with the exception of total T4, which was below normal limits at study end. In conclusion, 10 mg/kg twice daily results in peak plasma zonisamide which exceeds the recommended human therapeutic range (10 to 40 microg/mL) and is associated with suppression of thyroid hormone synthesis. A reasonable b.i.d starting dose for canine epileptics would be 3 mg/kg. Zonisamide monitored in either serum or plasma should be implemented at approximately 7 days.

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