Pharmacokinetics and Pharmacodynamics of Morphine and its Major Metabolites Following Intravenous Administration of Four Doses to Horses

Abstract

ObjectiveTo understand the pharmacokinetics of morphine and correlate the serum values of morphine and its metabolites to pharmacodynamic data.Materials and MethodsUsing a balanced randomized 5‐way crossover design; ten horses received an intravenous injection of saline and morphine at doses of 0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg, and 0.5 mg/kg. This was repeated until all horses received all treatments. A minimum washout period of 2 weeks was observed between treatments. Blood samples were collected at various time post drug administration, concentrations of morphine, M3G and M6G determined using liquid chromatography‐mass spectrometry and pharmacokinetic analysis performed. Horses were outfitted with step counters and Holter monitors. Gastrointestinal borborygmi, respiration, defecation, and overall demeanor were assessed. Concentrations of parent compound, M3G and M6G were correlated to pharmacodynamic data to better understand the effects of the active metabolites.ResultsMorphine is metabolized into two metabolites in the horse: morphine‐ 6 glucuronide (M6G) and morphine‐3 glucuronide (M3G). Both metabolites and parent compound were detected in the serum as soon as 5 minutes after administration. M3G was found in much higher concentrations than both M6G and parent compound. Concentrations of metabolites and parent compound were dose dependent with the highest concentrations seen in the 0.5 g/kg dose group. Plasma concentrations of morphine fit best in a three‐compartment model and were characterized by rapid distribution and slower elimination phases. Individual pharmacokinetic parameters for metabolites were obtained by noncompartmental analysis. Higher concentrations of M3G correlated with an increase in step count, increase in heart rate, and decrease in gastrointestinal borborygmi seen in the high dose group.Conclusions and Potential ImpactThis project delivers basic pharmacokinetic and pharmacodynamic knowledge of morphine administration to horses and provides valuable information regarding morphine metabolism in horses and the characteristics of these metabolites. The large amount of M3G may be contributing to the neuroexcitatory effects seen in horses after high doses of morphine. Further exploration of the individual effects of the metabolites would be helpful in potentially identifying a novel analgesic. This would be a large advance in veterinary medicine as the number of analgesics available to equine patients currently is limited an often come with severe side effects such as renal failure, gastrointestinal slowing, and increased CNS activity.Support or Funding InformationCalifornia Horse Racing Board Pharmacology Research FundsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.