Pharmacokinetics of pioglitazone after multiple oral dose administration in horses J. M. G. WEARN* M. V. CRISMAN* J. L. DAVIS   R. J. GEOR à ,1 D. R. HODGSON* J. K. SUAGEE à M. ASHRAF-KHORASSANI § L. J. MC CUTCHEON – ,2 *Department of Large Animal Clinical Sciences, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA;  Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA; àDepartment of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; §Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; –Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Leesburg, VA, USA Wearn, J. M. G., Crisman, M. V., Davis, J. L., Geor, R. J., Hodgson, D. R., Suagee, J. K., Ashraf-Khorassani, M., McCutcheon, L. J. Pharmacokinetics of pioglitaz- one after multiple oral dose administration in horses. J. vet. Pharmacol. Therap. 34, 252–258. Pioglitazone is a thiazolidinedione class of antidiabetic agent with proven efficacy in increasing insulin sensitivity in humans with noninsulin-dependent diabetes mellitus, a syndrome of insulin resistance sharing similarities with equine metabolic syndrome. The purpose of this study was to determine the pharma- cokinetics of pioglitazone in adult horses following multiple oral dose adminis- tration. Pioglitazone hydrochloride (1 mg ⁄ kg) was administered orally for 11 doses at 24-h intervals, and plasma samples were collected. Initially, a pilot study was performed using one horse; and thereafter the drug was administered to six horses. Samples were analyzed by liquid chromatography with tandem mass spectrometry, and pharmacokinetic parameters were calculated using noncompartmental modeling. The maximum plasma concentration was 509.1 ± 413.5 ng ⁄ mL achieved at 1.88 ± 1.39 h following oral administration of the first dose, and 448.1 ± 303.5 ng ⁄ mL achieved at 2.83 ± 1.81 h (mean ± SD) following the eleventh dose. Apparent elimination half-life was 9.94 ± 4.57 and 9.63 ± 5.33 h after the first and eleventh dose, respectively. This study showed that in healthy horses, pioglitazone administered at a daily oral dose of 1 mg ⁄ kg results in plasma concentrations and total drug exposure approximating, but slightly below, those considered therapeutic in humans. (Paper received 17 February 2010; accepted for publication 4 June 2010) M. V. Crisman, Department of Large Animal Clinical Sciences, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA. Tel: (540) 231 4621; fax : (540) 231 1676; E-mail: farmuse@vt.edu 1 Present address: Department of Large Animal Clinical Sciences, D202 Veterinary Medical Center, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA. 2 Present address: Department of Pathobiology and Diagnostic Investigation, F 130G Veterinary Medical Center, College of Veterinary Medicine, Michigan State Univer- sity, East Lansing, MI, USA. INTRODUCTION Pioglitazone ([(±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl] methyl]-2,4-] thiazolidinedione monohydrochloride) is a member of the thiazolidinedione (TZD) class of oral antidiabetic agents used in human medicine to treat noninsulin-dependent (type 2) diabetes mellitus (NIDDM) by improving insulin sensitivity (Yamasaki et al., 1997; Miyazaki et al., 2001; Rosenblatt et al., 2001). In human medicine, pioglitazone is administered orally at 15 or 45 mg once daily dosing, and pharmacokinetic studies have been published (Eckland & Danhof, 2000; Kalliokoski et al., 2008). Thiazolidinediones (TZDs) are synthetic activators of the peroxisome proliferator–activated receptor-c (PPARc), a class of nuclear receptor (Willson et al., 2001). Pioglitazone binds to these receptors and acts as a transcription factor with regulatory action on more than 100 genes associated with glucose and lipid metabolism, and inflammation (Berger et al., 2003; Rangwala & Lazar, 2004). By modulating expression of these genes, TZDs improve insulin sensitivity and reduce hyperglycemia without affecting pancreatic b-cell insulin secretion, therefore minimizing the risk of inducing hypoglycemia (Aronoff et al., 2000; Eckland & Danhof, 2000). J. vet. Pharmacol. Therap. 34, 252–258. doi: 10.1111/j.1365-2885.2010.01217.x. 252 Ó 2010 Blackwell Publishing Ltd