Preliminary pharmacokinetics of morphine and its major metabolites following intravenous administration of four doses to horses

Abstract

The objective of the current study was to describe the pharmacokinetics of morphine and its metabolites following intravenous administration to the horse. A total of eight horses (two per dose group) received a single intravenous dose of 0.05, 0.1, 0.2, or 0.5 mg/kg morphine. Blood samples were collected up to 72 h postdrug administration, analyzed using LC-MS/MS and pharmacokinetic parameters determined. Behavior, step counts, and gastrointestinal activity were also assessed. The beta and gamma half-life for morphine ranged from 0.675 to 2.09 and 6.70 to 18.1 h, respectively, following administration of the four different IV doses. The volume of distribution at steady-state and systemic clearance ranged from 6.95 to 15.8 L/kg and 28.3 to 35.7 mL · min/kg, respectively. The only metabolites identified in blood samples were the primary metabolites identified in other species, 3-morphine-glucuronide and 6-morphine-glucuronide. Muscle fasciculations were observed at 0.2 and 0.5 mg/kg and ataxia noted at 0.5 mg/kg. Gastrointestinal activity was decreased in all dose groups (for up to 8 h in 7/8 horses and 24 h in one horse). This study extends previous studies and is the first report describing the metabolites of morphine in the horse. Plasma concentrations of morphine-3-glucuronide, a metabolite with demonstrated neuro-excitatory activity in mice, far exceeded that of morphine-6-glucuronide. Further study is warranted to assess whether the high levels of the morphine-3-glucuronide contribute to the dose-dependent excitation observed at high morphine doses.

Generation of phase II in vitro metabolites using homogenized horse liver

“…[13] Although the biotransformation of morphine has not been well studied in the horse, it has recently been reported that morphine-3-glucuronide is the major phase II metabolite in plasma with morphine-6-glucuronide being a minor metabolite. This finding is consistent with the in vivo results reported recently by Knych et al [14] In addition, two more glucuronide metabolites of morphine were observed, namely, desmethylmorphine glucuronide and hydroxymorphine glucuronide as derived from their accurate mass and product-ion spectra. This could be supported by the fact that when morphine was incubated with homogenized liver in the presence of PAPS, no morphine sulfate was detected.…”

Pharmacokinetics and selected pharmacodynamics of morphine and its active metabolites in horses after intravenous administration of four doses

“…The primary goal of the current study was to confirm and extend current knowledge regarding the metabolism, pharmacokinetics, and selected pharmacodynamics of morphine in healthy horses. A preliminary report was published previously, whereby the metabolism and pharmacokinetics of morphine when administered at 4 different doses (0.05, 0.1, 0.2, and 0.5 mg/kg) were described; however, the study size was small ( n = 2/dose group; Knych et al., ).…”

“…While the pharmacokinetics of morphine in the horse has been described previously (Combie, Nugent, & Tobin, ; Knych, Steffey, & McKemie, ), to the best of the authors’ knowledge, there is only a single study describing the metabolism of morphine in horses (Knych et al., ). Knych et al.…”

“…() identified 2 major metabolites, M3G and M6G, following administration of 4 different doses of morphine to horses. Compared to humans, horses produced almost twice as much M3G but similar concentrations of M6G (Knych et al., ). Although the study conducted by Knych et al.…”

“…Although the study conducted by Knych et al. () was the first to describe the metabolism of morphine in the horse following administration of several doses, results were from a small sample size. Therefore, the goal of the current study was to confirm results of the earlier study and extend knowledge about the metabolism, pharmacokinetics, and selective pharmacodynamics of morphine following intravenous administration to healthy horses.…”