Walker M C, Tong X, Brown S, Shorvon S D, Patsalos P N
University Department of Clinical Neurology, Institute of Neurology, London, UK.
Epilepsia. 1998 Mar;39(3):283-9. doi: 10.1111/j.1528-1157.1998.tb01374.x.
To determine whether repeat boluses of diazepam (DZP) lead to significant accumulation in the central nervous system and/or peripheral compartments, as repeat intravenous boluses of diazepam are commonly used in the treatment of status epilepticus (SE).
In a rat model that permits simultaneous serum and cerebrospinal fluid (CSF) sampling, we characterized the pharmacokinetics of DZP and its metabolite, desmethyldiazepam, in CSF and blood using HPLC. DZP was administered by intraperitoneal injection as either a single dose (20 or 30 mg/kg) or repeat doses (10 or 20 mg/kg x 3, 1 h apart).
After a single intraperitoneal dose, DZP was rapidly absorbed with a time to maximum concentration of 10 min. The serum concentrations then declined biexponentially. DZP rapidly entered the CSF, the CSF to serum ratio reached equilibrium within 10 min, and was equivalent to the ratio of free to total serum concentration. Repeated DZP dosing resulted in a threefold decrease in volume of distribution and clearance (p < 0.001). This was reflected in the CSF concentration data; however, after the third dose, the ratio of CSF to serum concentration, also increased greatly, representing further persistence of DZP in the CSF compartment.
Repeat dosing of DZP leads to substantial accumulation, and high, persistent serum and CSF concentrations, which may explain the toxic effects of repeat DZP dosing. Repeat dosing of DZP using a tapering protocol, however, may increase the effectiveness of DZP in treating SE by preventing relapses without substantially increasing toxicity.
由于地西泮重复静脉推注常用于治疗癫痫持续状态（SE），因此确定重复推注地西泮（DZP）是否会导致其在中枢神经系统和/或外周腔室中显著蓄积。
在一个允许同时采集血清和脑脊液（CSF）的大鼠模型中，我们使用高效液相色谱法（HPLC）对CSF和血液中DZP及其代谢产物去甲基地西泮的药代动力学进行了表征。DZP通过腹腔注射给药，分为单次剂量（20或30mg/kg）或重复剂量（10或20mg/kg×3，间隔1小时）。
单次腹腔给药后，DZP迅速吸收，达峰时间为10分钟。血清浓度随后呈双指数下降。DZP迅速进入CSF，CSF与血清的比值在10分钟内达到平衡，且与血清中游离浓度与总浓度的比值相当。重复给予DZP导致分布容积和清除率降低了三倍（p<0.001）。这在CSF浓度数据中得到了体现；然而，在第三次给药后，CSF与血清浓度的比值也大幅增加，表明DZP在CSF腔室中进一步持续存在。
重复给予DZP会导致大量蓄积，并使血清和CSF浓度升高且持续存在，这可能解释了重复给予DZP的毒性作用。然而，采用逐渐减量方案重复给予DZP可能会通过预防复发而提高DZP治疗SE的有效性，且不会大幅增加毒性。
