Berg S L, Balis F M, McCully C L, Parker G A, Murphy R F, Poplack D G
Pediatric Branch, National Cancer Institute, Bethesda, MD 20892.
Cancer Chemother Pharmacol. 1992;31(2):127-30. doi: 10.1007/BF00685099.
Because meningeal spread of both leukemia and solid tumors remains a difficult therapeutic problem, there is a compelling need to develop new agents for intrathecal administration. 5-Fluorouracil (5FU), an active anticancer agent, penetrates into the central nervous system to some degree following intravenous dosing. Significant systemic toxicity, however, is associated with this route of administration. Therefore, the pharmacokinetic behavior of 5FU following its intrathecal administration was studied in a rhesus monkey model. After a 10-mg intraventricular dose, the disappearance of the drug from ventricular cerebrospinal fluid was monoexponential, the half-life being 51 min; the area under the concentration-time curve (AUC) being greater than 18 mM h-1; and the peak ventricular 5FU concentrations ranging between 10 and 15 mM. After a 1-mg intralumbar dose, the AUC was 1235 microM h-1. No toxicity was observed following intraventricular administration of 5FU. After intralumbar administration of either a 10-mg or a 1-mg dose, however, local toxicity was observed in the lumbar spinal cord. These findings suggest that intrathecal administration of 5FU is not presently a feasible means of achieving cytotoxic cerebrospinal fluid concentrations.
由于白血病和实体瘤的脑膜播散仍然是一个棘手的治疗难题，因此迫切需要开发用于鞘内给药的新型药物。5-氟尿嘧啶（5FU）是一种活性抗癌药物，静脉给药后可在一定程度上渗透到中枢神经系统。然而，这种给药途径会产生显著的全身毒性。因此，在恒河猴模型中研究了5FU鞘内给药后的药代动力学行为。脑室内给予10mg剂量后，药物从脑室脑脊液中的消失呈单指数形式，半衰期为51分钟；浓度-时间曲线下面积（AUC）大于18mM·h-1；脑室5FU峰值浓度在10至15mM之间。腰段给予1mg剂量后，AUC为1235μM·h-1。脑室内给予5FU未观察到毒性。然而，腰段给予10mg或1mg剂量后，在腰段脊髓观察到局部毒性。这些发现表明，目前鞘内给予5FU并非实现脑脊液细胞毒性浓度的可行方法。
