Pharmacokinetics of the calcium-channel blocker diltiazem after a single intravenous dose in horses 1 C. C. SCHWARZWALD R. A. SAMS & J. D. BONAGURA Department of Veterinary Clinical Science, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA 1 Parts of this study were presented as a scientific poster at the ACVIM forum 2005 in Baltimore, MD. Schwarzwald, C. C., Sams, R. A., Bonagura, J. D. Pharmacokinetics of the calcium-channel blocker diltiazem after a single intravenous dose in horses. J. vet. Pharmacol. Therap. 29, 165–171. The pharmacokinetics of diltiazem were determined in eight healthy horses. Diltiazem HCl, 1 mg/kg i.v., was administered over 5 min. Venous blood samples were collected at regular intervals after administration. Plasma concentrations of diltiazem and desacetyldiltiazem were determined by high- performance liquid chromatography. A second, putative metabolite was detected, but could not be identified due to the lack of an authentic standard. Data were analyzed by nonlinear least-squares regression analysis. The median (minimum–maximum) peak plasma concentration of diltiazem was 727 (539– 976) ng/mL. Plasma diltiazem concentration vs. time data were best described by a two-compartment model with first-order drug elimination. The distribution half-life was 12 (6–23) min, the terminal half-life was 93 (73–161) min, the mean residence time was 125 (99–206) min, total plasma clearance was 14.4 (10.4–18.6) mL/kg/min, and the volume of distribution at steady-state was 1.84 (1.46–2.51) L/kg. The normalized ratio of the area under the curve (AUC) of desacetyldiltiazem to the AUC of diltiazem was 0.088 (0.062–0.179). The disposition of diltiazem in horses was characterized by rapid distribution and elimination and a terminal half-life shorter than reported in humans and dogs. Because of the reported low pharmacologic activity, plasma diltiazem metabo- lite concentrations were not considered clinically important. (Paper received 15 February 2006; accepted for publication 22 February 2006) Dr med. vet. Colin C. Schwarzwald, DACVIM, Department of Veterinary Clinical Sciences, The Ohio State University, 601 Vernon L. Tharp Street, Columbus, OH 43210, USA. E-mail: schwarzwald.4@osu.edu INTRODUCTION Diltiazem is a calcium-channel blocker, which is used in humans and dogs for the treatment of supraventricular dysrhythmias and for heart rate control in patients with atrial fibrillation (AF), atrial flutter, and atrioventricular (AV) nodal re-entry (Cooke & Snyder, 1998; Opie, 2001). Atrial fibrillation is the most common dysrhythmia affecting performance in horses (Reef et al., 1995). In contrast to humans and dogs with AF, the resting heart rate in horses with AF is usually within normal limits and no underlying structural heart disease can be identified. Quinidine sulfate, the drug of choice for conversion of AF to sinus rhythm in horses, often increases impulse conduction through the AV node and results in an increased ventricular response rate (Collatos, 1995; Reef et al., 1995; Nappi & Mason, 1996). Sustained, rapid supraventricular tachycardia is the most common severe side effect of quinidine therapy, affecting over 50% of all treated horses (Collatos, 1995; Reef et al., 1995). The underlying mechanisms leading to an increase in ventricular response rate during quinidine treatment include vagolytic drug effects and increased organization of atrial impulses causing a decrease in AV nodal concealment (Gelzer et al., 2000). An increase in sympathetic tone secondary to development of drug-related abdominal pain may further facilitate AV nodal conduction. Traditionally, digoxin has been used to control heart rate in horses with AF (Reef et al., 1995). However, digoxin has a narrow therapeutic index, a delayed onset of action, and is only partially effective for heart rate control in the presence of elevated sympathetic tone (Moise, 1999; Miyamoto et al., 2000; Opie & Gersh, 2001). Recently, we proposed that diltiazem might be used as an alternative to digoxin for heart rate control in horses treated with quinidine (Schwarzwald et al., 2005). Our studies investigated the hemo- dynamic effects of diltiazem administered to healthy horses and demonstrated that the cardiac effects of diltiazem, at doses between 1 and 2 mg/kg i.v., include intermittent depression of the sinus and AV nodes, mild impairment of systolic and diastolic left ventricular function, arterial vasodilation, decreased J. vet. Pharmacol. Therap. 29, 165–171, 2006. Ó 2006 The Authors. Journal compilation Ó 2006 Blackwell Publishing Ltd 165