Boström Emma, Simonsson Ulrika S H, Hammarlund-Udenaes Margareta
Department of Biopharmaceutical Sciences, Division of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala, Sweden.
J Pharm Sci. 2005 May;94(5):1060-6. doi: 10.1002/jps.20327.
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 0.3 mg/kg oxycodone as a 1-h infusion. Plasma samples were taken, and tail-flick latency was monitored during the infusion and for 2 h 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.
本研究的目的是调查P-糖蛋白（P-gp）抑制剂PSC833对大鼠体内羟考酮的血浆药代动力学、全脑浓度及甩尾潜伏期的影响。每组8只大鼠，分别接受PSC833输注或不含PSC833的赋形剂输注。1小时后，所有动物均接受0.3mg/kg羟考酮，输注1小时。采集血浆样本，并在输注期间及之后2小时监测甩尾潜伏期。实验结束时收集大脑。两组在从时间零点到无穷大的血浆羟考酮浓度-时间曲线下面积、羟考酮血浆清除率、稳态分布容积或半衰期方面均无差异。在180分钟时，两组的平均全脑羟考酮浓度无差异，PSC833组和对照组的平均甩尾潜伏期也无差异。总之，联合使用PSC833并未改变羟考酮的血浆药代动力学、脑浓度或相关的甩尾潜伏期，这表明羟考酮在大鼠中不是P-gp底物。这具有重要的临床意义，因为这表明与其他一些阿片类药物不同，羟考酮不会在血脑屏障（BBB）处与同时给药的P-gp底物发生相互作用。
