Effects of a potent and specific P-glycoprotein inhibitor on the blood-brain barrier distribution and antinociceptive effect of morphine in the rat.
Effects of a potent and specific P-glycoprotein inhibitor on the blood-brain barrier distribution and antinociceptive effect of morphine in the rat.
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发表时间：
1999-07
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通讯作者：
Stephen P. Letrent;G. Pollack;Kenneth R. Brouwer;Kim L. R. Brouwer
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作者：
Stephen P. Letrent;G. Pollack;Kenneth R. Brouwer;Kim L. R. Brouwer
先前的数据表明，吗啡的镇痛作用可能是由P-糖蛋白（P-gp）抑制调制。在大鼠脑微透析模型上观察了P-gp抑制剂GF 120918对吗啡脑内分布的影响及吗啡的镇痛作用。用GF 120918预处理增加脑细胞外液（ECF）中未结合吗啡的浓度-时间曲线下面积和吗啡相关的抗伤害感受。脑ECF中未结合吗啡与血液中未结合吗啡的浓度-时间曲线下面积比在GF 120918处理的大鼠中显著高于对照大鼠（分别为1.21 +/-0.34对0.47 +/-0.05; p <0.05）。通过在单独一组大鼠中定量脑组织吗啡来证实吗啡脑-血分布的调节; GF 120918使脑组织：血清浓度比增加约3倍。脑ECF中未结合吗啡的半衰期在GF 120918处理的大鼠中比对照组长约3倍（p <0.05）。与对照组（0.662 +/-0.035）相比，在GF 120918存在下，全血中吗啡的未结合分数（0.651 +/-0.039）没有显著改变。与对照组相比，GF 120918处理的大鼠血液和脑ECF中未结合吗啡-3-葡糖苷酸的浓度增加。开发了一个综合的药代动力学/药效学模型，以表征未结合的血液和脑ECF吗啡浓度曲线和浓度-效应关系。这项研究的结果表明，改变吗啡抗伤害感受的一个有效的P-gp抑制剂似乎是介导的血脑屏障的水平。
Previous data suggest that the analgesic effect of morphine may be modulated by P-glycoprotein (P-gp) inhibition. The effects of the P-gp inhibitor GF120918 on brain distribution and antinociceptive effects of morphine were examined in a rat cerebral microdialysis model. Pretreatment with GF120918 increased both the area under the concentration-time curve of unbound morphine in brain extracellular fluid (ECF) and morphine-associated antinociception. The area under the concentration-time curve ratio for unbound morphine in brain ECF versus unbound morphine in blood was significantly higher in GF120918-treated rats compared with control rats (1.21 +/- 0.34 versus 0.47 +/- 0.05, respectively; p <.05). Modulation of morphine brain-blood distribution was confirmed by quantitating brain tissue morphine in a separate group of rats; GF120918 increased the brain tissue:serum concentration ratio approximately 3-fold. The half-life of unbound morphine in brain ECF was approximately 3-fold longer in GF120918-treated rats compared with controls (p <.05). The fraction unbound of morphine in whole blood was not altered significantly in the presence of GF120918 (0.651 +/- 0.039) as compared with controls (0.662 +/- 0.035). Concentrations of unbound morphine-3-glucuronide in blood and brain ECF were increased in GF120918-treated rats versus controls. An integrated pharmacokinetic/pharmacodynamic model was developed to characterize the unbound blood and brain ECF morphine concentration profiles and concentration-effect relationships. The results of this study indicate that alteration of morphine antinociception by a potent P-gp inhibitor appears to be mediated at the level of the blood-brain barrier.