Pharmacokinetics of phenobarbital in dogs after multiple oral administration.

Sodium phenobarbital (PHB) was administered orally as tablets 3 times a day to 6 healthy mature dogs of mixed breeding for 5 days at a dose of 2 mg/kg of body weight. On the 6th day, PHB was administered at 9 AM and venous blood samples were collected at 0, 1, 2, 3, 4, 6, 8, 10, 12, 14, 23, 35, 47, 59, 71, 83, 95, 107, 119, and 131 hours. Additional PHB was not given on day 6. Drug serum concentrations were described by a 1-compartment model with first-order absorption and elimination with fitted correlation coefficients of 0.991 +/- 0.007 (mean +/- SD). The observed PHB half-lives were between 37.3 and 74.6 hours with a mean of 53.0 +/- 15 hours. The calculated volume of distribution (Vd/F) was 743.6 +/- 69.8 ml/kg, and the total body clearance (ClT/F) was 0.173 +/- 0.053 ml/min/ kg. The absorption half-life was 1.27 +/- 0.21 hours. Based on the observed biological half-life after 5 days of dosing, approximately 11 days (8 to 15.5 days) of multiple dosing would be required to achieve steady-state serum concentrations. From average values, predicted maintenance doses of 1.8 mg/kg of body weight 3 times a day or 5.5 mg/kg once daily would be required to achieve average serum concentrations of 20 microg/ml. Due to intersubject variations in ClT/F, these doses would result in subtherapeutic or toxic serum concentrations in 2 of the 6 dogs. Further disposition and dosing regimen studies need to be performed during chronic PHB administration in dogs to evaluate autoinduction and intersubject differences in disposition kinetics.