Pharmacokinetics of phenobarbital in dogs given multiple doses

Abstract

SUMMARY Studies were conducted to examine the temporal changes an phenobarbital pharmacokinetics during chronic dosing in dogs. Ten dogs were allotted into 2 groups, administered a single oral dose, rested for 35 days, and then given the drug for 90 consecutive days. After single administration of 5.5 mg/kg of body weight or 15 mg/kg, the total body clearance (Clt/F) was 5.58 ± 1.89 ml/h/kg and 7.28 ± 1.07 ml/h/kg, respectively. The half-lives (t 1/2 ) for the 2 groups were 88.7 ± 19.6 hours for the 5.5-mg/kg dose and 99.6 ± 22.6 hours for the 15-mg/kg dose. Significant differences in Clt/F or t 1/2 were not observed between the 2 groups. Multiple-dosing regimens (5.5 mg/kg/day or 11 mg/kg/day) were initiated in the same dogs for 90 days. The Clt/F was significantly ( P < 0.05) greater on days 30, 60, and 90 than the single dose for both groups. After the last dose on day 90, several blood samples were obtained to determine phenobarbital t 1/2 . On day 90, the t 1/2 was significantly ( P < 0.05) shorter and the Clt/F was significantly greater than single-dose values. The Clt/F and t 1/2 were 10.2 ± 1.7 ml/h/kg and 47.3 ± 10.7 hours for the group given the low dose and 15.6 ± 2.5 ml/h/kg and 31.1 ± 4.4 hours for the group given the high dose, respectively. Both Clt/F and t 1/2 were significantly ( P < 0.05) different between the 2 groups on day 90. Results of the study indicated that single-dose pharmacokinetic studies of phenobarbital do not accurately predict steady-state phenobarbital serum concentrations (Css) because of possible autoinduction. Although considerable variation in phenobarbital pharmacokinetics was detected among dogs, a dose of 5.5 mg/kg/day is recommended for Css of 20 to 25 μg/ml and 11 mg/kg/day for Css of 30 to 40 μg/ml.