PHARMACOKINETICS OF NIMUSTINE, METHOTREXATE, AND CYTOSINE-ARABINOSIDEDURING CEREBROSPINAL-FLUID PERFUSION CHEMOTHERAPY IN PATIENTS WITH DISSEMINATED BRAIN-TUMORS

Objective: This study was conducted to evaluate the pharmacokinetics o f anticancer drugs in cerebrospinal fluid (CSF) perfusion chemotherapy . Methods: We administered CSF perfusion chemotherapy with nimustine ( ACNU), methotrexate (MTX), and cytosine arabinoside (Ara-C) to three p atients with disseminated malignant brain disease. The drugs were infu sed via Ommaya's reservoirs to the lateral ventricle and removed by dr ainage from the temporal lobe or lumbar spine. CSF and plasma concentr ations of the anticancer drugs were determined by high-performance liq uid chromatography and fluorescence polarization immunoassay. Results: The concentrations of anticancer drugs in the discharged CSF peaked a bout 40 min after the start of a 1-h CSF perfusion. After the perfusio n, the drug level in CSF decreased exponentially in a monophasic manne r. ACNU and Ara-C were not detectable in the discharged CSF in the tem poral lobe at 6 h and 48 h after perfusion, respectively, but MTX was detectable at 48 h. The maximum concentration ratio of anticancer drug s and the duration of perfusion were inversely correlated. The plasma concentrations of anticancer drugs were much lower than those in CSF. The half-life of ACNU was very short (0.2-1.1 h), whereas the half-liv es of MTX and Ara-C were relatively long (2.81-13.5 h and 1.84-6.25 h, respectively). The half-lives of the anticancer drugs in CSF tended t o decrease with repeated CSF perfusion chemotherapy. Conclusion: Resul ts suggest that CSF perfusion chemotherapy enables a high concentratio n of anticancer drug to be administered for dissemination in the spina l cord within a short period of time, with minimal adverse effects.