Pharmacokinetics and bioavailability of topiramate in the beagle dog.
Male and female beagle dogs showed rapid absorption following oral administration of single oral gavage (40 mg/kg) and single or multiple (15 days) oral capsule (10, 40, and 150 mg/kg) doses of the novel anticonvulsant drug, topiramate, with the peak plasma concentration (Cmax) occurring between 0.6 and 3.8 hr. The absolute bioavailability of an oral dose of topiramate was estimated to be in the range of 27-59%, depending on the formulation. The mean topiramate Cmax values increased in a dose-proportional manner for both single (9.2-137.7 micrograms/ml) and multiple (10.3-145.2 micrograms/ml) oral capsule administrations, whereas the corresponding area under the plasma concentration vs. time curve (AUC) values increased in a dose-related but nonproportional manner for both single (51-1131 micrograms.hr/ml) and multiple (54-858 micrograms.hr/ml) doses. Over the 10-150 mg/kg dosing range, oral plasma clearance and terminal half-life values were found to be 2.4-3.6 ml/min/kg and 2.6-3.7 hr following a single oral administration, and 3.0-4.2 ml/min/kg and 2.0-3.8 hr after multiple doses. There were no significant differences between the pharmacokinetic parameters calculated following the first and fifteenth daily doses of topiramate at the 10 and 40 mg/kg levels, indicating that there was no accumulation and no autoinduction or inhibition of enzymes that metabolize topiramate resulting from multiple dosing at these levels. A slight (24%) decrease in AUC was observed at the 150 mg/kg level after the fifteenth daily dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Streeter
A J
AJ
Department of Drug Metabolism, R.W. Johnson Pharmaceutical Research Institute, PA 19477-0776.
Stahle
P L
PL
Holland
M L
ML
Pritchard
J F
JF
Takacs
A R
AR
D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005260:Female; D005632:Fructose / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006207:Half-Life; D007408:Intestinal Absorption; D008297:Male; D011485:Protein Binding; D000077236:Topiramate
D000927:Anticonvulsants; D001798:Blood Proteins; D000077236:Topiramate; D005632:Fructose