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

This report investigates the pharmacokinetics of nimustine (ACNU), cytosine arabinoside (Ara-C), and methotrexate (MTX) in cerebrospinal fluid (CSF) during CSF perfusion chemotherapy. A 47-year-old Japanese man with spinal cord, cerebellum and brain stem dissemination of oligo-astrocytoma received nine courses of CSF perfusion chemotherapy with ACNU, Ara-C, and MTX. A CSF perfusion chemotherapy solution was perfused via an Ommaya reservoir in the ventricle, and was discharged by drainage though another Ommaya reservoir in the lumbar spinal canal. CSF samples via Ommaya reservoirs in the lumbar spinal canal were obtained during the fifth and eighth courses of treatment. The concentrations of ACNU and Ara-C in CSF were measured by HPLC, and the MTX concentrations by fluorescence polarization immunoassay. In the fifth course of treatment, a CSF injection chemotherapy solution, consisting of 5 mg of ACNU dissolved in 20 ml of artificial CSF, was injected over a few minutes using the Ommaya reservoir. Next, a CSF perfusion chemotherapy solution, consisting of 10 mg of Ara-C and 5 mg of MTX dissolved in 100 ml of artificial CSF, was perfused over 2 h. In the eighth course of treatment, a CSF perfusion chemotherapy solution, consisting of 5 mg of ACNU, 10 mg of Ara-C and 5 mg of MTX dissolved in 100 ml of artificial CSF, was perfused over 2 h. In both treatments, the highest concentrations of Ara-C and MTX in CSF were observed 1 or 2 h after the end of perfusion, with the values of each drug being similar. The CSF AUCs of Ara-C and MTX in each treatment were of similar values. Although the highest concentration of ACNU in CSF was observed in the fifth treatment 1 h after injection (an injection chemotherapy of ACNU plus a perfusion chemotherapy of Ara-C and MTX), the concentration of ACNU in CSF was undetectable in the eighth treatment (a perfusion chemotherapy of ACNU, Ara-C and MTX). We were successful in administering all anticancer drugs, and reaching a level of over 1.0 microg/ml concentration in CSF of the lumbar spinal canal, using an injection chemotherapy of ACNU plus a perfusion chemotherapy of Ara-C and MTX; this was done even though the drugs, in particular ACNU, underwent some perfusion-period dependent decomposition.

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 cerebrospinal fluid (CSF) during CSF perfusion chemotherapy. A 28-year-old Japanese woman with disseminated glioblastoma was, on admission, on a stable oral regimen of prolonged-release VPA tablets (Depakene-R), 400 mg twice a day, for seizure control. Twelve courses of CSF perfusion chemotherapy with Ara-C, MTX, and ACNU were administered. Plasma samples and CSF samples via Ommaya reservoirs were obtained during the eleventh course of treatment. The Ara-C and ACNU concentrations were measured by HPLC. The MTX and VPA concentrations were measured by fluorescence polarization immunoassay. During CSF perfusion chemotherapy, 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 0.71 h, respectively. No anticancer drugs were detectable in plasma during CSF perfusion chemotherapy. Before CSF perfusion chemotherapy, the free VPA concentration in plasma was 14.4% of the total VPA concentration. The mean total and free VPA concentrations in plasma were 78.0+/-0.8 and 10.9-0.3 microg/ml, respectively. The free VPA concentrations in plasma and in CSF were of similar values. At the end of perfusion, the lowest free VPA concentration in CSF was 30.3% of that at the initiation of perfusion. The free VPA concentrations in CSF at 3, 7, 23, and 47 h after the end of perfusion were 79.8, 94.5, 100.9, and 100.9% respectively of that at the initiation of perfusion. During CSF perfusion chemotherapy, the ratio of free VPA concentrations to the total VPA in CSF was 86.3+/-6.9%. The VPA concentrations in CSF rapidly decreased during the CSF perfusion but recovered to pre-treatment levels within 7 h.

Pharmacokinetics of anticancer drugs in cerebrospinal fluid.

OBJECTIVE: To examine the pharmacokinetics of anticancer drugs in the cerebrospinal fluid (CSF) during chemotherapy by the lumbar-ventricular (LV) and ventricular-lumbar (VL) routes. CASE SUMMARY: A 69-year-old Japanese woman with disseminated glioblastoma received two LV and four VL courses of CSF perfusion chemotherapy with methotrexate, nimustine, and cytarabine hydrochloride. Samples of CSF from the ventricles and lumbar spinal canal were obtained via Ommaya reservoirs during one LV and one VL course. Drug concentrations in the CSF were measured by fluorescence polarization immunoassay or HPLC. RESULTS: During LV CSF perfusion, the highest CSF drug concentrations in both the ventricles and the lumbar spinal canal were observed at the end of perfusion. During treatment, the concentrations of all three drugs in the lumbar spinal canal were higher than those in the ventricles. The CSF AUC of methotrexate in the ventricles was 16.1% of that in the lumbar spinal canal. During VL CSF perfusion, the highest drug concentrations were also observed at the end of perfusion. The drug concentrations in the lumbar spinal canal were initially lower than those in the ventricles. However, the concentrations of methotrexate and cytarabine in the lumbar spinal canal exceeded those in the ventricles 3 hours after perfusion. The AUC of methotrexate in the lumbar spinal canal was 174.9% of that in the ventricles. CONCLUSIONS: The pharmacokinetics of anticancer drugs in ventricular CSF differ from those in lumbar CSF during LV and VL perfusion chemotherapy.

Neurotoxicity and pharmacokinetics of intrathecal perfusion of ACNU in dogs.

To test the feasibility of intrathecal perfusion of ACNU (3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitro sou rea hydrochloride) in the treatment of subarachnoid dissemination of malignant glioma, the neurotoxicity and pharmacokinetics of ACNU were studied in dogs. ACNU [1-2 mg dissolved in 10-20 ml of lactated Ringer's solution or artificial cerebrospinal fluid (CSF)] was administered via the right lateral ventricle by constant drip infusion and CSF was drained by lumbar puncture. The infusion time was from 15 to 71 min. For the control, a bolus injection was given. No neurological and systemic symptoms were noted after perfusion. Histological examination of the brain and spinal cord revealed only mild denudation of ependyma in the wall of the ventricles in a dog treated three times with 2 mg ACNU (perfusion twice, bolus injection once) and in 2 dogs perfused with 1 mg ACNU once a week for 10 weeks. ACNU was not detected in lumbar CSF after bolus injection into the lateral ventricle. When 1 mg of ACNU, dissolved in 10 ml of artificial CSF, was perfused for a duration of 22 to 31 min, it started to appear in the lumbar CSF 10 to 15 min after the start of perfusion, reaching a maximum concentration of 13.88 to 22.31 micrograms/ml. The area under the drug concentration-time curve was 344 to 706 micrograms x min/ml; the half-time was 15.5 to 19.5 min. The distribution volume was 30.6 to 54.1 ml. These findings suggest the feasibility of intrathecal perfusion of ACNU in the treatment of patients with subarachnoid dissemination of glioma.