1578 AJVR, Vol 66, No. 9, September 2005 A utoimmune diseases, such as hemolytic anemia, thrombocytopenia, and pemphigus foliaceus, can present veterinarians with a therapeutic dilemma when they occur in horses. 1–8 In other species, such as humans and dogs, a number of immunosuppressive agents have been shown to be effective and relatively safe for the treatment of autoimmune disease. 9,10 Unfortunately, corticosteroids and injectable gold salts are the only immunosuppressive treatments that have been used with any frequency in horses. 1,5,7,8 Although these agents are often effective, the high doses of corti- costeroids necessary for successful treatment are asso- ciated with an increased risk of adverse effects, includ- ing steroid hepatopathy, laminitis, and iatrogenic hyperadrenocorticism. 8,11 Therefore, an investigation of additional immunosuppressive therapeutic agents to treat autoimmune diseases in horses is needed. Azathioprine (AZA) is an imidazole derivative of 6-mercaptopurine (6-MP) that is commonly used in humans and dogs to treat autoimmune diseases and to prevent rejection of organ transplants 9,10,12,13 It is a pro- drug that is converted in the blood, liver, and other organs to 6-MP, which is subsequently metabolized by hypoxanthine-guanine phosphoribosyltransferase into 6-thioinosine monophosphate. This metabolic route ultimately leads to the formation of pharmacologically active 6-thioguanine nucleotides (6-TGNs), which act as fraudulent nucleotides disrupting DNA and RNA synthesis, thereby inhibiting cellular proliferation and reducing antibody production and lymphocyte num- bers. 10,12,13 Elimination of the drug from the body is dependent upon metabolism of 6-MP to inactive metabolites by either xanthine oxidase or thiopurine methyltransferase (TPMT). 13,14 This latter enzyme appears to be critical, as genetically determined defi- ciencies of TPMT in humans correlate well with the incidence of myelosuppression, an adverse effect also observed in dogs and cats. 14–16 Other reported adverse effects in small animals include infection, hepatitis, pancreatitis, diarrhea, vomiting, and alopecia. 9,12 Several reports 2–4,7,8 indicate that AZA may be an effective alternative immunosuppressive agent in hors- es when corticosteroid administration is unsuccessful. The clinical experience of one of the authors (SDW) also supports AZA as effective in the treatment of hors- es with autoimmune diseases that are intolerant of high doses of corticosteroids or in the treatment of horses with autoimmune diseases that are refractory to corti- costeroid treatment alone. Although AZA appears to be a promising immunosuppressive agent in horses, its basic pharmacokinetic parameters and the tolerance of horses to the drug during chronic administration have yet to be established. The objectives of the study reported here were to determine the pharmacokinetics Received October 4, 2004. Accepted December 17, 2004. From the Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA 95616 (White, Hawkins); College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078 (Maxwell); Analytical Toxicology Core Laboratory, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611 (Szabo); and the Racing Laboratory, College of Veterinary Medicine, Gainesville, FL 32610 (Kollias-Baker). Dr. Hawkins’ current address is Reisterstown 24-Hour Veterinary Complex, 501 E Main St, Reisterstown, MD 21136. Address correspondence to Dr. White. Pharmacokinetics of azathioprine following single-dose intravenous and oral administration and effects of azathioprine following chronic oral administration in horses Stephen D. White, DVM; Lara K. Maxwell, DVM, PhD; Nancy J. Szabo, PhD; Jocelyn L. Hawkins, DVM; Cynthia Kollias-Baker, DVM, PhD Objective—To determine pharmacokinetics of azathio- prine (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 treat- ments. 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 adminis- tered 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 deter- mination and serum biochemical analysis. Results—Plasma concentrations of AZA and its metabolite, 6-MP, decreased rapidly from plasma fol- lowing 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 determina- tion or serum biochemical analysis, other than 1 horse that was lymphopenic on day 5 and 26 of daily treat- ment. 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 dis- eases in horses is warranted. (Am J Vet Res 2005;66:1578–1583) Unauthenticated | Downloaded 08/15/22 07:48 AM UTC