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.