Pharmacodynamic effects and pharmacokinetic profile of a long-term continuous rate infusion of racemic ketamine in healthy conscious horses
by
Lankveld DP, Driessen B, Soma LR, Moate PJ, Rudy J,
Uboh CE, VAN Dijk P, Hellebrekers LJ.
Equine Sciences Department,
Faculty of Veterinary Medicine,
Utrecht University,
Utrecht, The Netherlands.
J Vet Pharmacol Ther. 2006 Dec;29(6):477-88.

ABSTRACT

Ketamine (KET) possesses analgesic and anti-inflammatory activity at sub-anesthetic doses, suggesting a benefit of long-term KET treatment in horses suffering from pain, inflammatory tissue injury and/or endotoxemia. However, data describing the pharmacodynamic effects and safety of constant rate infusion (CRI) of KET and its pharmacokinetic profile in nonpremedicated horses are missing. Therefore, we administered to six healthy horses a CRI of 1.5 mg/kg/h KET over 320 min following initial drug loading. Cardiopulmonary parameters, arterial blood gases, glucose, lactate, cortisol, insulin, nonesterified fatty acids, and muscle enzyme levels were measured, as were plasma concentrations of KET and its metabolites using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Levels of sedation and muscle tension were scored. Respiration and heart rate significantly increased during the early infusion phase. Glucose and cortisol significantly varied both during and after infusion. During CRI all horses scored 0 on sedation. All but one horse scored 0 on muscle tension, with one mare scoring 1. All other parameters remained within or close to physiological limits without significant changes from pre-CRI values. The mean plasma concentration of KET during the 1.5 mg/kg/h KET CRI was 235 ng/mL. The decline of its plasma concentration-time curve of both KET and norketamine (NKET) following the CRI was described by a two-compartmental model. The metabolic cascade of KET was NKET, hydroxynorketamine (HNK), and 5,6-dehydronorketamine (DHNK). The KET median elimination half-lives (t(1/2alpha) and t(1/2beta)) were 2.3 and 67.4 min, respectively. The area under the KET plasma concentration-time curve (AUC), elimination was 76.0 mug.min/mL. Volumes of C(1) and C(2) were 0.24 and 0.79 L/kg, respectively. It was concluded that a KET CRI of 1.5 mg/kg/h can safely be administered to healthy conscious horses for at least 6 h, although a slight modification of the initial infusion rate regimen may be indicated. Furthermore, in the horse KET undergoes very rapid biotransformation to NKET and HNK and DHNK were the major terminal metabolites.

Memory
Ketamine
Beyond the K-hole
Ketamine: long-term outcomes
Ketamine: medical and non-medical use
The role of ketamine in pain management
Low-dose ketamine as a fast-onset, long-acting antidepressant