A new method for determination of in vivo pA2 using infusions of naloxone to steady-state blood concentrations.
A method is described for the measurement of pA2 in vivo for the opioid antagonist naloxone, infused to predicted steady-state blood concentrations in rats. The method has been applied to antagonism of the respiratory depressant effects of opioid agonists. The basis of the technique rests upon determination of the plasma clearance of the antagonist whence appropriate loading doses and zero order infusion rate constants are calculated. The predicted concentrations of naloxone were verified by direct plasma measurement. Using the infusion protocol pA2 determinations by Schild analysis were significantly different from those obtained by bolus injection. The approach described provides more accurate estimates of in vivo pA2 and could be applied to other antagonists, species, and biological responses, overcoming many of the problems inherent in the use of bolus antagonist dosing, which is currently widely employed.
D015760:Alfentanil; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors; D000818:Animals; D001667:Binding, Competitive; D002851:Chromatography, High Pressure Liquid; D004336:Drug Antagonism; D005283:Fentanyl / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D006207:Half-Life; D007262:Infusions, Intravenous; D008297:Male; D009020:Morphine / Q000037:antagonists & inhibitors; D009270:Naloxone / Q000097:blood* / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D012119:Respiration / Q000187:drug effects; D013997:Time Factors
D000701:Analgesics, Opioid; D015760:Alfentanil; D009270:Naloxone; D009020:Morphine; D005283:Fentanyl