Pharmacokinetic profile and behavioral effects of gabapentin in the horse R. L. TERRY* S. M. MC DONNELL* A. W. VAN EPS* L. R. SOMA* Y. LIU   C. E. UBOH   P. J. MOATE à & B. DRIESSEN* ,§ *Department of Clinical Studies-New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, USA;   Pennsylvania Equine Toxicology and Research Center, West Chester University, West Chester, PA, USA; à Department of Primary Industries, Ellinbank Centre, Ellinbank, VIC, Australia; § Department of Anesthesiology, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA, USA Terry, R. L., McDonnell, S. M., van Eps, A. W., Soma, L. R., Liu, Y., Uboh, C. E., Moate, P. J., Driessen, B. Pharmacokinetic profile and behavioral effects of gabapentin in the horse. J. vet. Pharmacol. Therap. 33, 485–494. Gabapentin is being used in horses although its pharmacokinetic (PK) profile, pharmacodynamic (PD) effects and safety in the equine are not fully investigated. Therefore, we characterized PKs and cardiovascular and behav- ioral effects of gabapentin in horses. Gabapentin (20 mg ⁄ kg) was administered i.v. or p.o. to six horses using a randomized crossover design. Plasma gabapentin concentrations were measured in samples collected 0–48 h postadministration employing liquid chromatography-tandem mass spectrometry. Blood pressures, ECG, and sedation scores were recorded before and for 12 h after gabapentin dosage. Nineteen quantitative measures of behaviors were evaluated. After i.v. gabapentin, the decline in plasma drug concentration over time was best described by a 3-compartment mammillary model. Terminal elimination half-life (t 1 ⁄ 2c ) was 8.5 (7.1–13.3) h. After p.o. gabapentin terminal elimination half-life (t 1=2e ) was 7.7 (6.7–11.9) h. The mean oral bioavailability of gabapentin (±SD) was 16.2 ± 2.8% indicating relatively poor absorption of gabapentin following oral administration in horses. Gabapentin caused a significant increase in sedation scores for 1 h after i.v. dose only (P < 0.05). Among behaviors, drinking frequency was greater and standing rest duration was lower with i.v. gabapentin (P < 0.05). Horses tolerated both i.v. and p.o. gabapentin doses well. There were no significant differences in t 1=2c and t 1=2e . Oral administration yielded much lower plasma concentrations because of low bioavailability. (Paper received 3 September 2009; accepted for publication 6 November 2009) Dr Bernd Driessen, Associate Professor of Anesthesiology, Dipl. ACVA & ECVPT, Department of Clinical Studies-NBC, School of Veterinary Medicine, University of Pennsylvania, 382 West Street Road, Kennett Square, PA 19348, USA. E-mail: driessen@vet.upenn.edu INTRODUCTION Gabapentin, [1-(aminomethyl)cyclohexaneacetic acid, C 9 H 17 NO 2 , M.W. 171.24], is an anti-epileptic drug licensed in human medicine since 1993 and is used as an adjunctive therapy for refractory partial seizures (Kong & Irwin, 2007). More recently the drug has also been used in humans to treat a variety of neuropathic pain states and early postsurgical pain (Maneuf et al., 2006; Gilron, 2007). In performance horses, gabapentin is listed as a class 3 performance-enhancing substance by the Association of Racing Commissioners International (Lehner et al., 2007). Despite being a structural analog of gamma-aminobutyric acid (GABA), gabapentin does not appear to bind to GABA-A or GABA-B receptors or to high affinity GABA transporters (Taylor et al., 1998; Jensen et al., 2002). While still incompletely understood, gabapentin’s anticonvulsive and analgesic mecha- nisms of action are thought to involve the inhibition of neurotransmitter release within the peripheral and central nervous system (CNS) through interaction with the a 2 -d accessory subunit of voltage-gated calcium channels (Gee et al., 1996; Baillie & Power, 2006; Maneuf et al., 2006). The expression of the a 2 -d subunit has been shown to increase in chronic pain states, as well as in both afferent sensory neurons and the spinal dorsal horn in experimental neuropathic pain models (Luo et al., 2001; Newton et al., 2001). This correlates well with the observation that gabapentin primarily demon- strates analgesic properties in sensitized or hyperalgesic states (Pan et al., 1999; Maneuf et al., 2006). Gabapentin has also been shown to inhibit the processes of temporal summation and spinal cord ‘wind-up’ in healthy human volunteers (Harding et al., 2005; Arendt-Nielsen et al., 2007), thus prompting its use as a perioperative analgesic (Gilron, 2007). Markers of neuronal injury are up-regulated in the digital nerves and dorsal root ganglia of horses with laminitis (Jones et al., 2007). Gabapentin therefore may provide or be adjunctive in providing analgesia in horses with laminitis, neuropathic or chronic pain states. J. vet. Pharmacol. Therap. 33, 485–494. doi: 10.1111/j.1365-2885.2010.01161.x. Ó 2010 Blackwell Publishing Ltd 485