Preliminary study of the pharmacokinetics, tissue distribution, and behavioral and select physiological effects of morphine 6-glucuronide (M6G) following intravenous administration to horses.

Abstract

Although morphine has demonstrated antinociceptive effects in horses, its administration has been associated with dose-dependent adverse effects. In humans and rats, part of the analgesic effect of morphine has been attributed to the active metabolite, morphine-6-glucuronide (M6G). Although morphine can cause several undesirable effects, M6G has a more favorable safety profile. The objective of this study was to characterize the pharmacokinetics, tissue distribution, and behavioral and select physiological effects of M6G following intravenous administration to a small group of horses. In Part 1 of the study, 3 horses received a single intravenous administration of saline, 0.5 mg/kg body weight (BW) M6G, or 0.5 mg/kg BW morphine in a 3-way crossover design. Blood samples were collected up to 96 hours post-administration, concentrations of drug and metabolites measured, and pharmacokinetics determined. Behavioral and physiological effects were then recorded. In Part 2 of the study, 2 horses scheduled to be euthanized for other reasons, were administered 0.5 mg/kg BW M6G. Blood, cerebrospinal fluid (CSF), and various tissue samples were collected post-administration and concentrations of drug were determined. The clearance of M6G was more rapid and the volume of distribution at steady state was smaller for M6G compared to morphine. A reaction characterized by head shaking, pawing, and slight ataxia was observed immediately following administration of both morphine and M6G to horses. After M6G administration, these behaviors subsided rapidly and were followed by a longer period of sedation. Following administration, M6G was detected in the kidney, liver, CSF, and regions of the brain. Results of this study encourage further investigation of M6G in order to assess its clinical feasibility as an analgesic in horses.