Pharmacokinetics of nimustine, methotrexate, and cytosine arabinoside during cerebrospinal fluid perfusion chemotherapy in patients with disseminated brain tumors

Abstract

Objective: This study was conducted to evaluate the pharmacokinetics of 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 patients with disseminated malignant brain disease. The drugs were infused via Ommaya's reservoirs to the lateral ventricle and removed by drainage from the temporal lobe or lumbar spine. CSF and plasma concentrations of the anticancer drugs were determined by high-performance liquid chromatography and fluorescence polarization immunoassay.

Results: The concentrations of anticancer drugs in the discharged CSF peaked about 40 min after the start of a 1-h CSF perfusion. After the perfusion, the drug level in CSF decreased exponentially in a monophasic manner. ACNU and Ara-C were not detectable in the discharged CSF in the temporal lobe at 6 h and 48 h after perfusion, respectively, but MTX was detectable at 48 h. The maximum concentration ratio of anticancer drugs 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-lives 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 to decrease with repeated CSF perfusion chemotherapy.

Conclusion: Results suggest that CSF perfusion chemotherapy enables a high concentration of anticancer drug to be administered for dissemination in the spinal cord within a short period of time, with minimal adverse effects.