Pharmacokinetics of an immediate and extended release oral morphine formulation utilizing the spheroidal oral drug absorption system in dogs

Abstract

This study investigated the pharmacokinetics of a human-labeled oral morphine formulation consisting of both immediate and extended release components in dogs. In a randomized design, 14 dogs were administered either 1 or 2 mg/kg morphine orally. Blood samples were collected up to 24 h post drug administration. Plasma concentrations of morphine were measured using high-pressure liquid chromatography with electrochemical coulometric detection. For both groups, maximal concentration occurred at 3 h post drug administration followed by a gradual decrease in morphine concentration over 24 h. There was substantial variability in morphine concentrations among dogs. The higher dose group produced a greater exposure (higher area-under-the-curve), higher peak concentration, longer half-life and a shorter time to peak concentration (t(max)). The specific oral morphine formulation used in this study produced sustained plasma morphine concentrations over 24 h compared with previous intravenous dosing and immediate-release oral morphine studies. However, the low morphine plasma concentrations and high variability produced from this formulation, suggest that the clinical application of this formulation at the doses evaluated in this study are limited.

The influence of modulation of P‐glycoprotein and /or Cytochrome P450 3A on the pharmacokinetics and pharmacodynamics of orally administered morphine in dogs

“…There was a large individual variability in the pharmacokinetic parameters after oral morphine administration in the different groups of the present study (Table 1). This has also been reported previously in dogs, both after administration of sustained-and non-sustained-release oral morphine formulations (Dohoo et al, 1994;Dohoo, 1997;KuKanich et al, 2005;Aragon et al, 2009). Overall, it is difficult to compare the data of the present with those reported in previous studies, mainly because of the application of different formulations and doses of morphine.…”

The present and future of opioid analgesics in small animal practice

“…Oral administration of opioids has shown low bioavailability, large individual variability, erratic gastrointestinal absorption, and limited analgesic effect particularly in dogs (Dohoo & Tasker, ; KuKanich et al ., ; Aragon et al ., ). Studies on the metabolism of morphine, hydrocodone, and codeine after oral administration indicate that metabolic and elimination pathways may be different in humans and dogs (Yeh et al ., ; Cone et al ., , ) along with a more vigorous first‐pass effect in dogs (Garrett & Jackson, ); it explains why bioavailability and analgesic efficacy of these drugs are dramatically different between these species.…”

The degradation and clearance of Poly(N-hydroxypropyl-l-glutamine)-DTPA-Gd as a blood pool MRI contrast agent

“…We chose poly( N -hydroxypropyl-L-glutamine) (PHPG) as the backbone on which to construct a polymeric MRI contrast agent. PHPG has been proven to be biodegradable, possesses excellent water solubility, and is neutral (nonionic), with low osmolality as well as numerous functional hydroxyl groups for chemical conjugation [11, 12]. …”