Pharmacokinetics of pentoxifylline and its 5-hydroxyhexyl metabolite after intravenous administration of increasing doses to sheep

OBJECTIVE To determine the pharmacokinetics of pentoxifylline (PTX) and its 5-hydroxyhexyl metabolite (M-I) after IV administration of increasing doses of PTX to sheep. ANIMALS 6 healthy adult Merino sheep. PROCEDURES Each sheep received 10-, 20-, and 40-mg/kg doses of PTX, IV, with a 15-day washout period between doses. Blood samples were collected before and at predetermined times after administration of each dose to determine plasma PTX and M-I concentrations by high-performance liquid chromatography. Pharmacokinetic parameters for PTX and M-I were estimated by noncompartmental analysis. RESULTS No adverse effects were observed after administration of the 10- and 20-mg/kg doses. Following administration of the 40-mg/kg dose, all sheep developed tachycardia and hypersalivation and appeared agitated for approximately 4 hours. Plasma PTX concentrations considered therapeutic in other species were achieved in all sheep after administration of all 3 doses. Pharmacokinetic parameters for PTX and M-I varied in a dose-dependent linear manner. For PTX, the mean area under the concentration-time curve (AUC), elimination half-life, and volume of distribution increased with dose and ranged from 15.67 to 94.66 h.mu g/mL, 0.68 to 0.91 hours, and 0.55 to 0.66 L/kg, respectively, whereas clearance decreased with dose and ranged from 0.42 to 0.64 L/h/kg. The mean ratio of the AUC for M-I to AUC for PTX ranged from 0.38 to 0.46. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that pharmacokinetic parameters for PTX and M-I varied in a dose-dependent linear manner in healthy sheep. Further studies are warranted to determine the therapeutic threshold and optimal dosage for PTX in sheep.