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Disposition, elimination, and bioavailability of phenytoin and its major metabolite in horses

Lawrence R. SomaSchool of Veterinary Medicine, University of Pennsylvania, New Bolton Center Campus, Kennett Square, PA 19348.

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Cornelius E. UbohSchool of Veterinary Medicine, University of Pennsylvania, New Bolton Center Campus, Kennett Square, PA 19348.
Pennsylvania Equine Toxicology and Research Laboratory, Department of Chemistry, West Chester University, West Chester, PA 19382.

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Fuyu GuanSchool of Veterinary Medicine, University of Pennsylvania, New Bolton Center Campus, Kennett Square, PA 19348.

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Eric K. BirksSchool of Veterinary Medicine, University of Pennsylvania, New Bolton Center Campus, Kennett Square, PA 19348.

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Donna C. TeleisSchool of Veterinary Medicine, University of Pennsylvania, New Bolton Center Campus, Kennett Square, PA 19348.

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Jeffrey A. RudyPennsylvania Equine Toxicology and Research Laboratory, Department of Chemistry, West Chester University, West Chester, PA 19382.

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Deborah S. TsangSchool of Veterinary Medicine, University of Pennsylvania, New Bolton Center Campus, Kennett Square, PA 19348.

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Anthony O. WatsonPennsylvania Equine Toxicology and Research Laboratory, Department of Chemistry, West Chester University, West Chester, PA 19382.

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Abstract

Objective—To determine pharmacokinetics and excretion of phenytoin in horses.

Animals—6 adult horses.

Procedure—Using a crossover design, phenytoin was administered (8.8 mg/kg of body weight, IV and PO) to 6 horses to determine bioavailability (F). Phenytoin also was administered orally twice daily for 5 days to those same 6 horses to determine steadystate concentrations and excretion patterns. Blood and urine samples were collected for analysis.

Results—Mean (± SD) elimination half-life following a single IV or PO administration was 12.6 ± 2.8 and 13.9 ± 6.3 hours, respectively, and was 11.2 ± 4.0 hours following twice-daily administration for 5 days. Values for F ranged from 14.5 to 84.7%. Mean peak plasma concentration (Cmax) following single oral administration was 1.8 ± 0.68 µg/ml. Steady-state plasma concentrations following twice-daily administration for 5 days was 4.0 ± 1.8 µg/ml. Of the 12.0 ± 5.4% of the drug excreted during the 36-hour collection period, 0.78 ± 0.39% was the parent drug phenytoin, and 11.2 ± 5.3% was 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH). Following twice-daily administration for 5 days, phenytoin was quantified in plasma and urine for up to 72 and 96 hours, respectively, and p-HPPH was quantified in urine for up to 144 hours after administration. This excretion pattern was not consistent in all horses.

Conclusion and Clinical Relevance—Variability in F, terminal elimination-phase half-life, and Cmax following single or multiple oral administration of phenytoin was considerable. This variability makes it difficult to predict plasma concentrations in horses after phenytoin administration. (Am J Vet Res 2001;62:483–489)

Abstract

Objective—To determine pharmacokinetics and excretion of phenytoin in horses.

Animals—6 adult horses.

Procedure—Using a crossover design, phenytoin was administered (8.8 mg/kg of body weight, IV and PO) to 6 horses to determine bioavailability (F). Phenytoin also was administered orally twice daily for 5 days to those same 6 horses to determine steadystate concentrations and excretion patterns. Blood and urine samples were collected for analysis.

Results—Mean (± SD) elimination half-life following a single IV or PO administration was 12.6 ± 2.8 and 13.9 ± 6.3 hours, respectively, and was 11.2 ± 4.0 hours following twice-daily administration for 5 days. Values for F ranged from 14.5 to 84.7%. Mean peak plasma concentration (Cmax) following single oral administration was 1.8 ± 0.68 µg/ml. Steady-state plasma concentrations following twice-daily administration for 5 days was 4.0 ± 1.8 µg/ml. Of the 12.0 ± 5.4% of the drug excreted during the 36-hour collection period, 0.78 ± 0.39% was the parent drug phenytoin, and 11.2 ± 5.3% was 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH). Following twice-daily administration for 5 days, phenytoin was quantified in plasma and urine for up to 72 and 96 hours, respectively, and p-HPPH was quantified in urine for up to 144 hours after administration. This excretion pattern was not consistent in all horses.

Conclusion and Clinical Relevance—Variability in F, terminal elimination-phase half-life, and Cmax following single or multiple oral administration of phenytoin was considerable. This variability makes it difficult to predict plasma concentrations in horses after phenytoin administration. (Am J Vet Res 2001;62:483–489)