PHARMACOKINETICS OF CHLORAMBUCIL-TERTIARY BUTYL ESTER, A LIPOPHILIC CHLORAMBUCIL DERIVATIVE THAT ACHIEVES AND MAINTAINS HIGH-CONCENTRATIONS IN BRAIN
PHARMACOKINETICS OF CHLORAMBUCIL-TERTIARY BUTYL ESTER, A LIPOPHILIC CHLORAMBUCIL DERIVATIVE THAT ACHIEVES AND MAINTAINS HIGH-CONCENTRATIONS IN BRAIN
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DOI：
10.1007/bf00686230
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发表时间：
1990-01-01
影响因子：
3
通讯作者：
RAPOPORT, SI
中科院分区：
文献类型：
--
作者：
GREIG, NH;DALY, EM;RAPOPORT, SI
静脉注射等摩尔剂量的苯丁酸氮芥 (10 mg/kg) 和亲脂性苯丁酸氮芥衍生物苯丁酸氮芥-叔丁酯 (13 mg/kg)。对老鼠来说。然后在给药后 2 至 240 分钟内通过 HPLC 测定苯丁酸氮芥及其活性代谢物、3,4-脱氢苯丁酸氮芥和苯乙酸芥子以及苯丁酸氮芥-叔丁酯的血浆和脑浓度。苯丁酸氮芥在给药后从血浆中单相消失，半衰期为 28 分钟。 15 分钟后检测到大量苯乙酸芥子气，并且在整个研究过程中，该试剂在血浆中保持高水平的活性化合物。 2 至 120 分钟之间，大脑中仅检测到低浓度的苯丁酸氮芥和苯乙酸芥子。等摩尔苯丁酸氮芥-叔丁酯给药后，它迅速从血浆中消失，半衰期约为2分钟，并在治疗后15至120分钟内保持较低的平台浓度。尽管在整个研究过程中检测到了大量的苯丁酸氮芥和苯乙酸芥子，但此后就没有检测到。大量苯丁酸氮芥叔丁酯进入并保留在大脑内，在 15 分钟时达到峰值浓度，此后消失，半衰期为 37 分钟。还检测到低含量的苯丁酸氮芥和苯乙酸芥子气。根据脑和血浆中苯丁酸氮芥和苯丁酸氮芥-叔丁酯衍生的总活性化合物的浓度与时间曲线下面积计算，脑：血浆浓度积分比分别为0.018和0.68。在等摩尔剂量的苯丁酸氮芥和苯丁酸氮芥-叔丁酯之后，苯丁酸氮芥-叔丁酯在脑中以低5倍的血浆浓度积分实现了7倍的浓度积分。苯丁酸氮芥-叔丁酯可能对治疗脑隔离肿瘤有价值。
Equimolar doses of chlorambucil (10 mg/kg) and the lipophilic chlorambucil derivative, chlorambucil-tertiary butyl ester (13 mg/kg), were given i.v. to rats. Plasma and brain concentrations of chlorambucil and its active metabolites, 3,4-dehydrochlorambucil and phenylacetic mustard, as well as of chlorambucil-tertiary butyl ester were then determined by HPLC between 2 and 240 min after drug administration. Chlorambucil demonstrated a monophasic disappearance from plasma following its adminstration, with a half-life of 28 min. Significant amounts of phenylacetic mustard were detected after 15 min, and this agent maintained high levels of active compounds in plasma throughout the study. Only low concentrations of chlorambucil and phenylacetic mustard were detected in brain between 2 and 120 min. Following equimolar chlorambucil-tertiary butyl ester administration, it rapidly disappeared from plasma, with a half-life of approximately 2 min, and maintained low plateau concentrations between 15 and 120 min after treatment. It was not detected thereafter, although significant amounts of chlorambucil and phenylacetic mustard, were detected throughout the study. Significant amounts of chlorambucil-tertiary butyl ester entered and remained within the brain, achieving a peak concentration at 15 min and disappearing thereafter with a half-life of 37 min. Low levels of chlorambucil and phenylacetic mustard were also detected. Calculated from the areas under the concentration vs time curves of total active compounds derived from chlorambucil and chlorambucil-tertiary butyl ester in brain and plasma, the brain:plasma concentration integral ratios were 0.018 and 0.68, respectively. Following equimolar doses of chlorambucil and chlorambucil-tertiary butyl ester, a 7-fold greater concentration integral was achieved by chlorambucil-tertiary butyl ester in brain at 5-fold lower plasma concentration integral. Chlorambucil-tertiary butyl ester may be of value in the treatment of brain sequestered tumors.