Oxycodone Pharmacokinetics and Pharmacodynamics in the Rat in the Presence of the P-Glycoprotein Inhibitor PSC833

Abstract

The objective of this study was to investigate the in vivo influence of the P-glycoprotein (P-gp) inhibitor PSC833 on the plasma pharmacokinetics, total brain concentrations and tail-flick latency of oxycodone in rats. Eight rats each received an infusion of PSC833 or vehicle without PSC833. One hour later, all animals received 0.3mg/kg oxycodone as a 1-h infusion. Plasma samples were taken, and tail-flick latency was monitored during the infusion and for 2h thereafter. The brains were collected at the end of the experiment. There were no differences between the two groups in area under the plasma oxycodone concentration-time curve from time zero to infinity, or oxycodone plasma clearance, volume of distribution at steady-state, or half-life. There were no differences in average total brain oxycodone concentrations at 180 min, nor were there any differences in average tail-flick latency for the PSC833 and control groups. In conclusion, coadministration of PSC833 did not alter the plasma pharmacokinetics, brain concentrations, or associated tail-flick latency of oxycodone, indicating that oxycodone is not a P-gp substrate in the rat. This has important clinical implications, as it indicates that oxycodone, unlike some other opioids, will not interact at the blood–brain barrier (BBB) with concomitantly administered P-gp substrates. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association