Pharmacokinetical Comparison of Anticancer Drugs in Cerebrospinal Fluid during Cerebrospinal Fluid Perfusion and Injection Chemotherapy

Abstract

The present study examined the pharmacokinetics of anticancer drugs in the cerebrospinal fluid (CSF) during CSF perfusion or injection chemotherapy. A 69-year-old Japanese woman with disseminated glioblastoma received one course of both ventricular-lumbar (V-L) and lumbarventricular (L-V) CSF perfusion chemotherapy, and one course of both ventricular and lumbar injection chemotherapy with methotrexate (MTX), cytosine arabinoside (Ara-C), and nimustine (ACNU). Samples of CSF from the ventricles and lumbar spinal canal were obtained via the Ommaya reservoirs. The drug concentrations in the CSF were measured by either fluorescence polarization immunoassay or high performance liquid chromatography. In the V-L CSF perfusion chemotherapy, the maximum CSF concentrations of the three drugs in the lumbar spinal canal were lower than those in the ventricles. However, the concentrations of MTX and Ara-C in the lumbar spinal canal exceeded those in the ventricles 3 hours after the perfusion. The area under the CSF concentration versus the time curves (AUC) of MTX and Ara-C in the lumbar spinal canal were 175.7 and 76.2%, respectively, of those in the ventricles. In the L-V CSF perfusion chemotherapy, the CSF concentrations of the three drugs in the lumbar spinal canal were higher than those in the ventricle. The AUCs of MTX and Ara-C in the ventricles were 15.5 and 18.4 %, respectively, of those in the lumbar spinal canal. In the ventricular CSF injection, the initial CSF concentrations of the three drugs in the ventricles were higher than those in the lumbar spinal canal. However, the CSF concentrations of MTX and Ara-C in the lumbar spinal canal exceeded those in the ventricles 12 hours after the injection. Although the concentration of ACNU in the ventricles was only detectable at 3 hours after the injection, no concentration in the lumbar spinal canal was detectable. The AUCs of MTX and Ara-C in the lumbar spinal canal were 84.6 and 29.1%, respectively, of those in the ventricles. In the lumbar CSF injection, the CSF concentrations of MTX and Ara-C in the ventricles were detectable but lower than those in the lumbar. Although the CSF concentration of ACNU in the lumbar spinal canal was only detectable at 3 hours after the injection, no concentration in the ventricles was detectable. The AUC of MTX in the ventricles was 0.31% of that in the lumbar spinal canal. These results indicate that CSF perfusion chemotherapy may thus be a more useful treatment than CSF injection chemotherapy to patients with disseminated brain tumors.