Duration of opioid antagonism by nalmefene and naloxone in the dog: an integrated pharmacokinetic/pharmacodynamic comparison.
A continuous fentanyl infusion was administered to eight adult, male beagle dogs for a duration of approximately 400 min at a rate of 30 micrograms/kg/h. The extent of respiratory depression was quantified by continuous, noninvasive, transcutaneous pCO2 recordings. Upon reaching a pseudosteady-state of respiratory depression at approximately 120 min of fentanyl infusion, the animals then received, in a 2 x 2 crossover fashion separated by approximately 3 weeks, 30-minute equiefficacious infusions of nalmefene (12 micrograms/kg/h) or naloxone (48 micrograms/kg/h). Multiple venous blood samples were taken throughout the dosing regimen, and the resulting fentanyl, nalmefene, or naloxone plasma concentrations were determined. The concentration-time data were analyzed by noncompartmental methods and subsequently linked to the pharmacodynamic effect data by a competitive antagonism link model. Separately, the biophase concentrations were linked to the plasma concentration-time profiles through a single-exponential conduction function. The various pharmacokinetic/pharmacodynamic parameters resulting from this semiparametric analysis were analyzed by ANOVA, using a statistical model that considers carryover effects. The results of these analyses indicate that several pharmacokinetic/pharmacodynamic parameters of the two antagonists were comparable. However, nalmefene had a significantly more protracted terminal disposition and a significantly greater persistency in the biophase evaluated over the experimental time frame from 0 to 450 min.
College of Pharmacy, University of Iowa, Iowa City 52242, USA.
P
P
Veng-Pedersen
J A
JA
Wilhelm
T B
TB
Zakszewski
E
E
Osifchin
S J
SJ
Waters
D000818:Animals; D001785:Blood Gas Monitoring, Transcutaneous; D004285:Dogs; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007262:Infusions, Intravenous; D008954:Models, Biological; D009270:Naloxone / Q000493:pharmacokinetics* / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology*; D009294:Narcotics / Q000008:administration & dosage / Q000494:pharmacology; D012119:Respiration / Q000187:drug effects
D009292:Narcotic Antagonists; D009294:Narcotics; D009270:Naloxone; D009271:Naltrexone; C038981:nalmefene; D005283:Fentanyl