Pharmacokinetics of phenobarbital in horses after single and repeated oral administration of the drug

D. A. Knox From the Departments of Physiology and Pharmacology (Knox, Nostrandt, Pedersoli), Pathology and Parasitology (Spano), Anatomy and Histology (Krista), Large Animal Medicine and Surgery (Schumacher), College of Veterinary Medicine and the Department of Pharmacal Sciences (Ravis), School of Pharmacy, Auburn University, AL 36849.

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W. R. Ravis From the Departments of Physiology and Pharmacology (Knox, Nostrandt, Pedersoli), Pathology and Parasitology (Spano), Anatomy and Histology (Krista), Large Animal Medicine and Surgery (Schumacher), College of Veterinary Medicine and the Department of Pharmacal Sciences (Ravis), School of Pharmacy, Auburn University, AL 36849.

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W. M. Pedersoli From the Departments of Physiology and Pharmacology (Knox, Nostrandt, Pedersoli), Pathology and Parasitology (Spano), Anatomy and Histology (Krista), Large Animal Medicine and Surgery (Schumacher), College of Veterinary Medicine and the Department of Pharmacal Sciences (Ravis), School of Pharmacy, Auburn University, AL 36849.

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J. S. Spano From the Departments of Physiology and Pharmacology (Knox, Nostrandt, Pedersoli), Pathology and Parasitology (Spano), Anatomy and Histology (Krista), Large Animal Medicine and Surgery (Schumacher), College of Veterinary Medicine and the Department of Pharmacal Sciences (Ravis), School of Pharmacy, Auburn University, AL 36849.

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A. C. Nostrandt From the Departments of Physiology and Pharmacology (Knox, Nostrandt, Pedersoli), Pathology and Parasitology (Spano), Anatomy and Histology (Krista), Large Animal Medicine and Surgery (Schumacher), College of Veterinary Medicine and the Department of Pharmacal Sciences (Ravis), School of Pharmacy, Auburn University, AL 36849.

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L. M. Krista From the Departments of Physiology and Pharmacology (Knox, Nostrandt, Pedersoli), Pathology and Parasitology (Spano), Anatomy and Histology (Krista), Large Animal Medicine and Surgery (Schumacher), College of Veterinary Medicine and the Department of Pharmacal Sciences (Ravis), School of Pharmacy, Auburn University, AL 36849.

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J. Schumacher From the Departments of Physiology and Pharmacology (Knox, Nostrandt, Pedersoli), Pathology and Parasitology (Spano), Anatomy and Histology (Krista), Large Animal Medicine and Surgery (Schumacher), College of Veterinary Medicine and the Department of Pharmacal Sciences (Ravis), School of Pharmacy, Auburn University, AL 36849.

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Summary

Six healthy mature horses were orally administered a single dose of phenobarbital (26 mg/kg of body weight), then multiple doses (13 mg/kg) orally for 42 consecutive days. Seventeen venous blood samples were collected from each horse after the single dose study and again after the last dose on day 42. Plasma phenobarbital concentration was determined by use of a fluorescence assay validated for horses. Additional blood samples (n = 11) were collected on days 8 and 25 to determine peak and trough concentrations, as well as total body clearance. Phenobarbital disposition followed a one-compartment model. Mean kinetic variables after single and repeated orally administered doses (42 days) were: elimination half-life = 24.2 ± 4.7 and 11.2 ± 2.3 hours, volume of distribution = 0.960 ± 0.060 and 0.914 ± 0.119 L/kg, and clearance = 28.2 ± 5.1 and 57.3 ± 9.6 ml/h/kg, respectively. Results indicated that significant (P < 0.05) difference in half-life and oral clearance existed between single and repeated dosing. The significant decrease in half-life after repeated dosing with phenobarbital may be indicative of enzyme induction. Significant difference was not observed between baseline serum enzyme concentration and concentration measured on day 42, except for γ-glutamyltransferase activity, which was significantly increased on day 42 in 3 of the 6 horses. On the basis of increases in oral clearance observed over 42 days, dose adjustments may be required. By days 25 to 42, pharmacokinetic values indicated that dosages of phenobarbital between 25 and 27 mg/kg administered orally every 24 hours may be needed to maintain steady state plasma concentration of phenobarbital at 20 μg/ml of plasma in mature horses.

Summary

Six healthy mature horses were orally administered a single dose of phenobarbital (26 mg/kg of body weight), then multiple doses (13 mg/kg) orally for 42 consecutive days. Seventeen venous blood samples were collected from each horse after the single dose study and again after the last dose on day 42. Plasma phenobarbital concentration was determined by use of a fluorescence assay validated for horses. Additional blood samples (n = 11) were collected on days 8 and 25 to determine peak and trough concentrations, as well as total body clearance. Phenobarbital disposition followed a one-compartment model. Mean kinetic variables after single and repeated orally administered doses (42 days) were: elimination half-life = 24.2 ± 4.7 and 11.2 ± 2.3 hours, volume of distribution = 0.960 ± 0.060 and 0.914 ± 0.119 L/kg, and clearance = 28.2 ± 5.1 and 57.3 ± 9.6 ml/h/kg, respectively. Results indicated that significant (P < 0.05) difference in half-life and oral clearance existed between single and repeated dosing. The significant decrease in half-life after repeated dosing with phenobarbital may be indicative of enzyme induction. Significant difference was not observed between baseline serum enzyme concentration and concentration measured on day 42, except for γ-glutamyltransferase activity, which was significantly increased on day 42 in 3 of the 6 horses. On the basis of increases in oral clearance observed over 42 days, dose adjustments may be required. By days 25 to 42, pharmacokinetic values indicated that dosages of phenobarbital between 25 and 27 mg/kg administered orally every 24 hours may be needed to maintain steady state plasma concentration of phenobarbital at 20 μg/ml of plasma in mature horses.

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