Blood-brain barrier transport and brain distribution of morphine-6-glucuronide in relation to the antinociceptive effect in rats-pharmacokinetic/pharmacodynamic modelling
Blood-brain barrier transport and brain distribution of morphine-6-glucuronide in relation to the antinociceptive effect in rats-pharmacokinetic/pharmacodynamic modelling
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DOI：
10.1038/sj.bjp.0704406
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发表时间：
2001-12-01
影响因子：
7.3
通讯作者：
Hammarlund-Udenaes, M
中科院分区：
文献类型：
--
作者：
Bouw, MR;Xie, RJ;Hammarlund-Udenaes, M
1本研究的目的是探讨血脑屏障转运在延缓吗啡-6-葡萄糖醛酸脂(M6G)抗伤害性反应中的作用，并用微透析法研究M6G在体内跨血脑屏障的平衡。2连续两天，大鼠以3000 ng ml(-1)(6.5um)为目标血药浓度，指数输注M6G 4h。用微透析法测定脑细胞外液(ECF)和静脉血中游离M6G的浓度，定期取样测定动脉血中游离M6G的浓度。3M6G在动脉血中的半衰期为23+/-5min，在静脉血中的半衰期为26+/-10min，在脑ECF中的半衰期为58+/-17min(P<；0.05，脑与血相比)。以非结合稳态浓度比表示的血脑屏障平衡为0.22+/-0.09，表明M6G的血脑屏障转运是主动的。两室模型最好地描述了M6G的脑分布。未结合体积为0.20±0.02mlg脑(-1)。M6G的浓度-抗伤害效应关系表现出明显的滞后，导致相对于血液浓度的效应延迟半衰期为103min，相对于脑ECF浓度的剩余效应延迟半衰期为53min。4 M6G的效应延迟的一半可以通过跨血脑屏障的转运来解释，提示剩余的53min的效应延迟是药物在脑组织内分布或受体水平的限速机制的结果。
1 The objective of this study was to investigate the contribution of the blood-brain barrier (BBB) transport to the delay in antinociceptive effect of morphine-6-glucuronide (M6G), and to study the equilibration of M6G in vivo across the BBB with microdialysis measuring unbound concentrations.2 On two consecutive days, rats received an exponential infusion of M6G for 4 h aiming at a target concentration of 3000 ng ml(-1) (6.5 muM) in blood. Concentrations of unbound M6G were determined in brain extracellular fluid (ECF) and venous blood using microdialysis and in arterial blood by regular sampling. MD probes were calibrated in vivo using retrodialysis by drug prior to drug administration.3 The half-life of M6G was 23 +/-5 min in arterial blood, 26 +/- 10 min in venous blood and 58 +/- 17 min in brain ECF (P < 0.05, brain vs blood). The BBB equilibration, expressed as the unbound steady-state concentration ratio, was 0.22 +/-0.09, indicating active efflux in the BBB transport of M6G. A two-compartment model best described the brain distribution of M6G. The unbound volume of distribution was 0.20 +/-0.02 ml g brain(-1). The concentration-antinociceptive effect relationships exhibited a clear hysteresis, resulting in an effect delay half-life of 103 min in relation to blood concentrations and a remaining effect delay half-life of 53 min in relation to brain ECF concentrations.4 Half the effect delay of M6G can be explained by transport across the BBB, suggesting that the remaining effect delay of 53 min is a result of drug distribution within the brain tissue or rate-limiting mechanisms at the receptor level.