Distribution of intrathecally administered ACNU in mongrel dogs: pharmacokinetics and quantitative autoradiographic...

The pharmacokinetics of 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) in the cerebrospinal fluid (CSF), were determined in dogs after ventriculolumbar perfusion (VLP, n = 6), and bolus injection into the ventricle (VB, n = 2), cisterna magna (MB, n = 5), and lumbar cistern (LB, n = 3), by high-performance liquid chromatography. The VLP method introduced effective amounts of ACNU into the lumbar cistern for cell kill in vitro. That is, the areas under the time concentration curve (AUC) of ACNU in the lumbar CSF for those receiving a 1.5 mg perfusion of ACNU were 481, 791, and 520 micrograms.min/ml and those receiving a 5 mg perfusion were 1,081, 2,048, and 1,215 micrograms.min/ml, respectively. These values were superior to 3-log cell kill condition of 9L gliosarcoma and 1.5-log cell kill of HU-126 human glioma cell line. Among the groups to which 5 mg of ACNU was administered, the VLP method attained significantly higher AUC values in the lumbar CSF than MB method. Quantitative autoradiography using an imaging plate system was performed in the VLP group (n = 2), VB group (n = 1), MB group (n = 2), and LB group (n = 2) using a 10 microCi/kg [ethylene-14C] ACNU dose which is thought to be related to the alkylating activity of ACNU. The VLP method attained a stable and abundant distribution of ACNU in the neural axis from the ventricular cavity to the lumbar cistern, but the cerebral convexity surface was devoid of a significant level of ACNU. When the MB method was used, the pharmacokinetic data varied in the cisterna magna and lumbar region, and again no significant level of ACNU was detected in the ventricular cavity. With the LB method, although a rich distribution was detected in the spinal cord, the concentration decreased abruptly at the upper cervical level. The VB method was unsatisfactory for obtaining an effective amount of ACNU in the lumbar region. The research and testing to date indicate that the VLP method is the procedure of choice in the treatment of meningeal dissemination.