Pharmacokinetics of cytosine arabinoside, methotrexate, nimustine and valproic acid in cerebrospinal fluid during cerebrospinal fluid perfusion chemotherapy

This report investigates the pharmacokinetics of cytosine arabinoside (Ara- C), methotrexate (MTX), nimustine (ACNU) and valproic acid (VPA) in cerebro spinal fluid (CSF) during CSF perfusion chemotherapy. Japanese woman with d isseminated glioblastoma was, on admission, on a stable oral regimen of pro longed-release VPA tablets (Depakene(TM)-R), 400 mg twice a day, for seizur e control. Twelve courses of CSF perfusion chemotherapy with Ara-C, MTX, an d ACNU were administered. Plasma samples and CSF samples via Ommaya reservo irs were obtained during the eleventh course of treatment. The Ara-C and AC RTU concentrations were measured by HPLC. The MTX and VPA concentrations we re measured by fluorescence polarization immunoassay. During CSF perfusion themotherapy, the highest CSF concentrations of Ara-C, MTX, and ACNU were observed at the end of the perfusion and decreased in a monoexponential pattern. The half-lives of Ara-C, MTX, and ACNU were 2.65, 3.52, and 0.71h, respectively. No anticancer drugs were detectable in plas ma during CSF perfusion chemotherapy. Before CSF perfusion chemotherapy; th e free VPA concentration in plasma was 14.4% of the total VPA concentration . The mean total and fi ee VPA concentrations in plasma were 78.0 +/- 0.8 a nd 10.9 +/- 0.3 mu g/ml, respectively. The free VPA concentrations in plasm a and in CSF were of similar values. At the end of perfusion, the lowest fr ee VPA concentration in CSF was 30.3% of that at the initiation of perfusio n. The free VPA concentrations in CSF at 3, 7, 23, and 47 h after the end o f perfusion were 79.8, 93.5, 100.9, and 100.9% respectively of that at the initiation of perfusion. During CSF perfusion chemotherapy, the ratio of fr ee VPA concentrations to the total VPA in CSF was 86.3 +/- 6.9%. The VPA co ncentrations in CSF rapidly decreased during the CSF perfusion but recovere d to pre-treatment levels within 7 h.