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Pharmacokinetics of azathioprine following single-dose intravenous and oral administration and effects of azathioprine following chronic oral administration in horses

Stephen D. WhiteDepartment of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA 95616.

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Lara K. MaxwellCollege of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078.

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Nancy J. SzaboAnalytical Toxicology Core Laboratory, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611.

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Jocelyn L. HawkinsDepartment of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA 95616.
Current address is Reisterstown 24-Hour Veterinary Complex, 501 E Main St, Reisterstown, MD 21136.

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Cynthia Kollias-BakerRacing Laboratory, College of Veterinary Medicine, Gainesville, FL 32610.

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Abstract

Objective—To determine pharmacokinetics of azathioprine (AZA) and clinical, hematologic, and serologic effects of IV and oral administration of AZA in horses.

Animals—6 horses.

Procedure—In study phase 1, a single dose of AZA was administered IV (1.5 mg/kg) or orally (3.0 mg/kg) to 6 horses, with at least 1 week between treatments. Blood samples were collected for AZA and 6-mercaptopurine (6-MP) analysis 1 hour before and at predetermined time points up to 4 hours after AZA administration. In study phase 2, AZA was administered orally (3 mg/kg) every 24 hours for 30 days and then every 48 hours for 30 days. Throughout study phase 2, blood samples were collected for CBC determination and serum biochemical analysis.

Results—Plasma concentrations of AZA and its metabolite, 6-MP, decreased rapidly from plasma following IV administration of AZA, consistent with the short mean elimination half-life of 1.8 minutes. Oral bioavailability of AZA was low, ranging from 1% to 7%. No horses had abnormalities on CBC determination or serum biochemical analysis, other than 1 horse that was lymphopenic on day 5 and 26 of daily treatment. This horse developed facial alopecia from which 1 colony of a Trichophyton sp was cultured; alopecia resolved within 1 month after the study ended.

Conclusions and Clinical Relevance—Overall, no adverse effects were observed with long-term oral administration of AZA to horses, although 1 horse did have possible evidence of immunosuppression with chronic treatment. Further investigation of the clinical efficacy of AZA in the treatment of autoimmune diseases in horses is warranted. (Am J Vet Res 2005;66:1578–1583)

Abstract

Objective—To determine pharmacokinetics of azathioprine (AZA) and clinical, hematologic, and serologic effects of IV and oral administration of AZA in horses.

Animals—6 horses.

Procedure—In study phase 1, a single dose of AZA was administered IV (1.5 mg/kg) or orally (3.0 mg/kg) to 6 horses, with at least 1 week between treatments. Blood samples were collected for AZA and 6-mercaptopurine (6-MP) analysis 1 hour before and at predetermined time points up to 4 hours after AZA administration. In study phase 2, AZA was administered orally (3 mg/kg) every 24 hours for 30 days and then every 48 hours for 30 days. Throughout study phase 2, blood samples were collected for CBC determination and serum biochemical analysis.

Results—Plasma concentrations of AZA and its metabolite, 6-MP, decreased rapidly from plasma following IV administration of AZA, consistent with the short mean elimination half-life of 1.8 minutes. Oral bioavailability of AZA was low, ranging from 1% to 7%. No horses had abnormalities on CBC determination or serum biochemical analysis, other than 1 horse that was lymphopenic on day 5 and 26 of daily treatment. This horse developed facial alopecia from which 1 colony of a Trichophyton sp was cultured; alopecia resolved within 1 month after the study ended.

Conclusions and Clinical Relevance—Overall, no adverse effects were observed with long-term oral administration of AZA to horses, although 1 horse did have possible evidence of immunosuppression with chronic treatment. Further investigation of the clinical efficacy of AZA in the treatment of autoimmune diseases in horses is warranted. (Am J Vet Res 2005;66:1578–1583)