BENZODIAZEPINE CONCENTRATIONS IN BRAIN DIRECTLY REFLECT RECEPTOR OCCUPANCY - STUDIES OF DIAZEPAM, LORAZEPAM, AND OXAZEPAM
BENZODIAZEPINE CONCENTRATIONS IN BRAIN DIRECTLY REFLECT RECEPTOR OCCUPANCY - STUDIES OF DIAZEPAM, LORAZEPAM, AND OXAZEPAM
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DOI：
10.1007/bf02244106
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发表时间：
1990-01-01
影响因子：
3.4
通讯作者：
SETHY, VH
中科院分区：
文献类型：
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作者：
GREENBLATT, DJ;SETHY, VH
雄性CF-1小鼠分别静脉注射3和10µm ol/kg地西潘、劳拉西潘和奥沙西潘。注射后1min~2 4h，用气相色谱(GLC)法测定血浆和一侧大脑半球的苯二氮卓类药物浓度，用~3H-氟硝西仑排泄法测定另一侧大脑半球的体外苯二氮卓类受体占有率。根据GLC数据，地西潘迅速进入大脑，也迅速被清除，在血浆和脑中产生去甲基安定和奥沙西潘作为代谢物。但劳拉西潘和奥沙西潘进入脑后缓慢，30~60min达到血浆平衡，此后药物同时从血浆和脑中排出。体外占用的时间进程和程度与GLC数据高度一致(对于地西潘，GLC水平表示为地西潘、去甲基地西潘和奥西潘的总和，与代谢物浓度、分子量和体外苯二氮卓类受体亲和力归一化)。方法间相关系数为0.95或更高。因此，苯二氮卓类受体的占位高度依赖于脑组织中的苯二氮卓类药物浓度。高亲脂性苯二氮卓类安定与亲脂性较差的羟化衍生物劳拉西潘和奥西潘之间的药理活性起效时间和持续时间的差异在很大程度上是由于全身动力学和脑摄取速度的差异。
Groups of male CF-1 mice received 3 and 10 .mu.mol/kg diazepam, lorazepam, and oxazepam intravenously. Between 1 min and 24 h after injection, benzodiazepine concentrations were determined by gas chromatography (GLC) in plasma and in one brain hemisphere; in the other hemisphere, ex vivo benzodiazepine receptor occupancy was measured using 3H-flunitrazepam displacement. Based on GLC data, diazepam entered brain rapidly, and was also cleared rapidly, yielding desmethyldiazepam and oxazepam as metabolites in plasma and brain. However, lorazepam and oxazepam entered brain slowly, with brain:plasma equilibrium achieved at 30-60 min; thereafter, the drugs were eliminated from plasma and brain in parallel. The time course and extent of ex vivo occupancy were highly consistent with GLC data (for diazepam, GLC levels were expressed as the sum of diazepam, desmethyldiazepam, and oxazepam, with metabolite concentrations, normalized for molecular weight and for in vitro benzodiazepine receptor affinity). Between-method correlations were 0.95 or higher. Thus benzodiazepine receptor occupancy is highly dependent on benzodiazepine concentrations in brain. Differences in the time-course of onset and duration of pharmacologic activity between the highly lipophilic benzodiazepine diazepam and the less lipophilic hydroxylated derivatives lorazepam and oxazepam are largely explained by differences in systemic kinetics and in the rate of uptake into brain.