EFFECT OF DIETARY OBESITY ON NALOXONE DISPOSITION IN SHEEP

Naloxone is an opioid antagonist used frequently in studies of appetite regulation in lean and obese animals and humans. Body condition may affect plasma and tissue distribution of injected naloxone and thus confound interpretation of responses to naloxone in lean compared with obese subjects. The objective of this experiment was to determine the effect of dietary obesity per se on the pharmacokinetic behavior of iv-injected naloxone (3 mg/kg) in lean (46 kg body weight) and dietary obese (77 kg body weight) sheep that were maintained at equilibrium weight. To this end, an HPLC procedure combined with electrochemical detection was developed for measuring naloxone in sheep plasma. Naloxone disappearance from plasma followed an apparent first-order process, the kinetics of which were described best using a two-compartment open model. Components of the biexponential equations describing the plasma concentration (C) - time (t) curves for naloxone disappearance in lean (C-t = 1814e(-0.190t) + 413e(-0.017t)) and obese (C-t = 2282e(-0.282t) + 573e(-0.018t)) sheep were similar (p > 0.05). Mean (+/-SE) elimination half-lifes for naloxone in lean (42.7 +/- 4.6 min) and obese (44.3 +/- 10.2 min) sheep were similar (p > 0.05). Volume of distribution of naloxone (V-d) was extensive but also similar (p > 0.05) in lean (5.6 +/- 0.9 L/kg) and obese (4.1 +/- 0.6 L/kg) sheep. Naloxone was distributed extensively throughout the body fluids and trapped or stored in significant amount in extravascular tissues because the naloxone V-d greatly exceeded 100% of body weight in both lean (557 +/- 86 mL/100 g) and obese (413 +/- 58 mL/100 g) sheep. Whole-body clearance (Cl-B) of naloxone indexed to body weight (90 +/- 7 vs. 69 +/- 6 mL.kg(-1).min(-1)) and absolute rates for body clearance (4.1 + 0.3 vs. 5.3 +/- 0.6 L/min) of naloxone tended to be greater (p < 0.1) in lean than obese sheep. We conclude that dietary obesity did not alter significantly the pharmacokinetic behavior of iv-injected naloxone in sheep.