BIOAVAILABILITY AND PHARMACOKINETICS OF INTRAVENOUSLY AND ORALLY-ADMINISTERED ALLOPURINOL IN HEALTHY BEAGLES

Objectives-To determine bioavailability and pharmacokinetic parameters for allopurinol and its active metabolite, oxypurinol. Animals-6 heal thy, reproductively intact female Beagles, 4.9 to 5.2 years old, and w eighing 9.5 to 11.5 kg. Procedure-In the first part of the study, allo purinol was administered IV at a dosage of 10 mg/kg of body weight to 3 dogs and 5 mg/kg to 3 dogs; the sequence was then reversed. In the s econd part of the study, allopurinol was administered orally at a dosa ge of 15 mg/kg to 3 dogs and 7.5 mg/kg to 3 dogs; the sequence was the n reversed. In the third part of the study, allopurinol was administer ed IV 110 mg/kg), orally 115 mg/kg) with food, and orally (15 mg/kg) w ithout food. Plasma samples were obtained at timed intervals, and conc entrations of allopurinol and oxypurinol were determined. Results-Maxi mal plasma allopurinol concentration and area under plasma allopurinol and oxypurinol concentration-time curves were 2 times greater when do gs were given 10 mg of allopurinol/kg IV, compared with 5 mg/kg, and w hen dogs were given 15 mg of allopurinol/kg orally, compared with 7.5 mg/kg. Allopurinol elimination half-life, time to reach maximal plasma oxypurinol concentration, and oxypurinol elimination half-life were s ignificantly greater when dogs received 10 mg of allopurinol/kg IV, co mpared with 5 mg/kg, and when dogs received 15 mg of allopurinol/kg or ally, compared with 7.5 mg/kg. Conclusions-Elimination of allopurinol is dependent on nonlinear enzyme kinetics. The bioavailability of allo purinol, and pharmacokinetic parameters of allopurinol and oxypurinol after oral administration of allopurinol, are not affected by administ ration with food. Clinical Relevance-A dose threshold exists beyond wh ich additional allopurinol would not substantially further inhibit xan thine oxidase activity. Oral administration of > 15 mg of allopurinol/ kg to dogs would not be expected to result in greater reduction of pla sma and urine uric acid concentrations. Also, allopurinol may be admin istered to dogs for dissolution or prevention of urate uroliths withou t regard to time of feeding.