Pharmacokinetic-pharmacodynamic modelling of morphine transport across the blood-brain barrier as a cause of the antinociceptive effect delay in rats -: A microdialysis study
Pharmacokinetic-pharmacodynamic modelling of morphine transport across the blood-brain barrier as a cause of the antinociceptive effect delay in rats -: A microdialysis study
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DOI：
10.1023/a:1026414713509
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发表时间：
2000-10-01
影响因子：
3.7
通讯作者：
Hammarlund-Udenaes, M
中科院分区：
文献类型：
--
作者：
Bouw, MR;Gårdmark, M;Hammarlund-Udenaes, M
目的。量化跨越血脑屏障(BBB)的分布过程对吗啡延缓大鼠抗伤害感受作用的贡献。使用微透析(MD)监测静脉血和脑细胞外液(ECF)中的游离吗啡浓度，并通过定期采样监测动脉血中的游离吗啡浓度。用药物反透析法对MD探针进行体内校准。静脉注射吗啡(10 mg/kg或40 mg/kg)10min以上。用电刺激发声法测定其痛觉，并测定其孵化气体状态。游离吗啡在纹状体的半衰期为44分钟，而在静脉和动脉血中的半衰期为30分钟(p<；0.05)。吗啡的血脑屏障平衡(纹状体与静脉血曲线下面积之比)小于1(10 mg/kg和40 mg/kg时分别为0.28±0.09和0.22±0.17)，表明吗啡跨血脑屏障主动外流。浓度-效应关系表现出明显的滞后效应，根据动脉血和脑内ECF浓度，半衰期分别延迟32min和5min。85%的效应延迟是由吗啡跨血脑屏障转运引起的，提示剩余的5min效应延迟可能涉及受体水平的限速机制或分布现象。
Purpose. To quantify the contribution of distributional processes across the blood-brain barrier (BBB) to the delay in antinociceptive effect of morphine in rats.Methods. Unbound morphine concentrations were monitored in venous blood and in brain extracellular fluid (ECF) using microdialysis (MD) and in arterial blood by regular sampling. Retrodialysis by drug was used for in vivo calibration of the MD probes. Morphine was infused (10 or 40 mg/kg) over 10 min intravenously. Nociception, measured by the electrical stimulation vocalisation method, and brood gas status were determined.Results. The half-life of unbound morphine in striatum was 44 min compared to 30 min in venous and arterial blood (p < 0.05). The BBB equilibration of morphine, expressed as the ratio of areas under the curve between striatum and venous blood, was less than unity (0.28 +/- 0.09 and 0.22 +/- 0.17 for 10 and 40 mg/kg), respectively, indicating active efflux of morphine across the BBB. The concentration-effect relationship exhibited a clear hysterisis with an effect delay half-life of 32 and 5 min based on arterial blood and brain ECF concentrations, respectively.Conclusions. Eighty five percent of the effect delay was caused by morphine transport across the BBB, indicating possible involvement of rate limiting mechanisms at the receptor level or distributional phenomena for the remaining effect delay of 5 min.