title: Disposition and safety of zonisamide after intravenous and oral single dose and oral multiple dosing in normal hound dogs.
abstract: 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.
authors.affiliation: Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, AL 36849-5518, USA. boothdm@auburn.edu
authors.forename: D M
authors.initials: DM
authors.lastname: Boothe
authors.forename: J
authors.initials: J
authors.lastname: Perkins
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D004285:Dogs; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006207:Half-Life; D007275:Injections, Intravenous; D007555:Isoxazoles / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D011485:Protein Binding; D013963:Thyroid Hormones / Q000097:blood; D000078305:Zonisamide
chemical_list: D000927:Anticonvulsants; D007555:Isoxazoles; D013963:Thyroid Hormones; D000078305:Zonisamide