Felbamate pharmacokinetics in the rat, rabbit, and dog.
Rats, rabbits, and dogs were given single iv or single and multiple oral doses of felbamate ranging from 1.6-1000 mg/kg. Absorption of oral drug was complete in all species. The mean Cmax increased with dose from 13.9 to 185.9 micrograms/ml in rats, from 19.1 to 161.9 micrograms/ml in rabbits, and from 12.6 to 168.4 micrograms/ml in dogs. The tmax also increased with dose from 1-8 hr in rats, 8-24 hr in rabbits, and 3-7 hr in dogs. The plasma elimination half-life for the drug increased with dose from 2-16.7 hr in rats, 7.2-17.8 hr in rabbits, and 4.1-4.5 hr in dogs. A proportional increase in Cmax with dose was observed in all species up to 300-400 mg/kg doses. A biexponential equation fitted the drug plasma concentration vs. time data well. For multiple oral doses of 50 mg/kg or less, projected and observed steady-state concentrations agreed well. Animals dosed with [14C]felbamate eliminated most of the radioactivity in urine (58-87.7%), less in feces (7-23.7%), with considerable amounts in the bile. In rats, radioactivity was readily distributed into tissues and crossed the placenta and blood-brain barrier, but no accumulation in any tissue was observed. The volume of distribution was 131, 54, and 72% of body weight for rats, rabbits, and dogs, respectively. Binding of drug to rat, rabbit, and dog plasma proteins ranged from 22.4-35.9%. The overall plasma clearance of the drug for rats, rabbits, and dogs was 327, 52, and 108 ml.h-1.kg-1, respectively. Renal clearance of unchanged drug accounted for an estimated 20-35% and hepatic clearance due to metabolism for 65-80% of the overall clearance.
Wallace Laboratories, Division of Carter-Wallace, Inc., Cranbury, NJ 08512.
V E
VE
Adusumalli
J T
JT
Yang
K K
KK
Wong
N
N
Kucharczyk
R D
RD
Sofia
D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D004285:Dogs; D000078328:Felbamate; D005260:Female; D007408:Intestinal Absorption; D007928:Lethal Dose 50; D008297:Male; D048448:Phenylcarbamates; D011247:Pregnancy; D011409:Propylene Glycols / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D000927:Anticonvulsants; D048448:Phenylcarbamates; D011409:Propylene Glycols; D000078328:Felbamate