Cytosine arabinoside cerebrospinal fluid kinetics

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Neuro-oncology
• Cerebrospinal Fluid Dynamics

Background:

• Meningeal leukemia requires effective central nervous system (CNS) chemotherapy.
• Understanding the disposition of intraventricular chemotherapy is crucial for optimizing treatment and minimizing systemic toxicity.
• Cytosine arabinoside (Ara-C) is a chemotherapeutic agent used in CNS leukemia, but its CSF kinetics require detailed characterization.

Purpose of the Study:

• To characterize the pharmacokinetic profile of cytosine arabinoside (Ara-C) in the cerebrospinal fluid (CSF) after intraventricular administration.
• To determine the elimination kinetics and primary clearance mechanisms of Ara-C in the CSF.
• To assess the extent of Ara-C metabolism within the CSF and its penetration into plasma.

Main Methods:

• Seven patients with meningeal leukemia in complete remission received intraventricular injections of 30 mg Ara-C.
• CSF and plasma samples were collected over 24 hours post-injection.
• Ara-C and its metabolite, uracil arabinoside (Ara-U), were quantified using a sensitive reverse-phase HPLC assay.

Main Results:

• CSF Ara-C elimination exhibited biphasic kinetics with half-lives of 1 hour (initial) and 3.4 hours (terminal).
• CSF clearance of Ara-C was determined to be 0.42 ml/min, consistent with elimination by CSF bulk flow.
• Metabolism of Ara-C to Ara-U in CSF was minimal (AUC ratio of 0.08), and Ara-C was undetectable in plasma despite high CSF concentrations.

Conclusions:

• Intraventricular administration of Ara-C leads to high and sustained concentrations within the CSF.
• CSF bulk flow is the predominant mechanism for Ara-C elimination from the CNS.
• Intraventricular Ara-C effectively targets the CNS while minimizing systemic exposure and toxicity.