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

Orhan Corum DVM, PhD1, Duygu Durna Corum DVM, PhD1, Orkun Atik DVM2, Ayse Er DVM, PhD3, and Kamil Uney DVM, PhD3
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  • 1 1Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Kastamonu, 37200, Kastamonu, Turkey.
  • | 2 2Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Afyon Kocatepe, 03200, Afyonkarahisar, Turkey.
  • | 3 3Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Selcuk, 42031, Konya, Turkey.

Abstract

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·μg/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.

Abstract

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·μg/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.

Contributor Notes

Address correspondence to Dr. Corum (orhancorum46@hotmail.com).