Hori T, Muraoka K, Saito Y, Sasahara K, Inagaki H, Inoue Y, Adachi S, Anno Y
J Neurosurg. 1987 Mar;66(3):372-8. doi: 10.3171/jns.1987.66.3.0372.
The water-soluble nitrosourea compound ACNU is also lipid-soluble at normal physiological pH levels. It lacks toxic effects on vision that nitrosoureas occasionally produce following intra-arterial administration. In 28 cases of both primary and secondary malignant brain tumors, ACNU was administered at surgery or angiography by three different modes: intravenous injection in Group I (10 cases), intra-arterial injection via the carotid artery in Group II (11 cases), and intra-arterial injection via the carotid artery after opening the blood-brain barrier (BBB) by means of mannitol in Group III (seven cases). Tumor tissue and blood samples were taken serially at various time intervals after ACNU injection, and ACNU was measured by high-performance liquid chromatography. The time-concentration curve for ACNU was calculated in each case by the two- and one-compartment open models for determination of ACNU levels in blood and tissue, respectively. Pharmacokinetic parameters including biological half-life, blood and tissue levels (0-t minutes and 0-infinity minutes), total plasma clearance, and distribution volume of the beta phase were compared. Statistical analysis of tissue ACNU levels at 0-t minutes revealed higher concentrations in Group III patients than in Groups II and I: levels in Group II were significantly higher than in Group I. Mean biological half-life was 30.3, 23.0, and 38.5 minutes in Groups I, II, and III, respectively. Levels of ACNU were significantly increased in tumor tissue as well as in peritumoral tissue in one Group III patient with multiple metastatic anaplastic adenocarcinoma. In this series, treatment of malignant brain tumor by intra-arterial administration of ACNU produced significantly higher tissue levels of ACNU than did the systemic intravenous route.
水溶性亚硝基脲化合物ACNU在正常生理pH值水平下也具有脂溶性。它没有亚硝基脲在动脉内给药后偶尔产生的对视神经的毒性作用。在28例原发性和继发性恶性脑肿瘤患者中，ACNU在手术或血管造影时通过三种不同方式给药：第一组（10例）静脉注射，第二组（11例）经颈动脉动脉内注射，第三组（7例）在通过甘露醇打开血脑屏障（BBB）后经颈动脉动脉内注射。在ACNU注射后的不同时间间隔连续采集肿瘤组织和血液样本，并通过高效液相色谱法测定ACNU。分别通过二室和一室开放模型计算每种情况下ACNU的时间 - 浓度曲线，以确定血液和组织中的ACNU水平。比较了包括生物半衰期、血液和组织水平（0 - t分钟和0 - 无穷大分钟）、总血浆清除率和β相分布容积在内的药代动力学参数。对0 - t分钟时组织ACNU水平的统计分析显示，第三组患者的浓度高于第二组和第一组；第二组的水平明显高于第一组。第一组、第二组和第三组的平均生物半衰期分别为30.3、23.0和38.5分钟。在一名患有多灶性间变性腺癌转移的第三组患者中，肿瘤组织以及瘤周组织中的ACNU水平显著升高。在本系列研究中，动脉内给予ACNU治疗恶性脑肿瘤产生的ACNU组织水平明显高于全身静脉途径。
