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

Objective-To determine pharmacokinetics and excretion of phenytoin in horse s. Animals-6 adult horses. Procedure-Using a crossover design, phenytoin was administered (8.8 mg/kg o f body weight, IV and PO) to 6 horses to determine bioavailability (F). Phe nytoin also was administered orally twice daily for 5 days to those same 6 horses to determine steady-state concentrations and excretion patterns. Blo od and urine samples were collected for analysis. Results-Mean (+/-SD) elimination half-life following a single IV or PO admi nistration was 12.6 +/- 2.8 and 13.9 +/- 6.3 hours, respectively, and was 1 1.2 +/- 4.0 hours following twice-daily administration for 5 days. Values f or F ranged from 14.5 to 84.7%. Mean peak plasma concentration (C-max) foll owing single oral administration was 1.8 +/- 0.68 mug/ml. Steady-state plas ma concentrations following twice-daily administration for 5 days was 4.0 /- 1.8 mug/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 twi ce-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. Conclusions and Clinical Relevance-Variability in F, terminal elimination-p hase half-life, and C-max following single or multiple oral administration of phenytoin was considerable. This variability makes it difficult to predi ct plasma concentrations in horses after phenytoin administration.