The relationship between pharmacokinetics and pharmacodynamic action as applied to in vivo pA2: application to the analgesic effect of morphine.
When the pA2 of an antagonist is determined in vivo, administered doses are used rather than the peak or steady-state tissue concentrations. The present report examines the error which can arise in this method and also presents a method for determining the pA2 from data obtained at times after peak. We applied this time-dependent analysis to time-dose-response data obtained with morphine-naloxone in the rat, using tail compression as the nociceptive stimulus. Good agreement between pA2 values was found: 8.0 with peak effect data, and 8.1 with the time-dependent method. Further, this analysis yielded 20 minutes as the half-life of naloxone. It is concluded that the time-dependent method provides a check on the pA2 in vivo and confirms the utility of this constant in classifying receptors. The appendix contains methodology for application to other agonist-antagonist combinations classified according to their kinetics.
D000700:Analgesics; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D009020:Morphine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D009270:Naloxone / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D013997:Time Factors
D000700:Analgesics; D009270:Naloxone; D009020:Morphine