Cytosine arabinoside cerebrospinal fluid kinetics

Abstract

To better characterize the disposition of cytosine arabinoside (Ara-C) in cerebrospinal fluid (CSF), its kinetics were studied in seven patients with meningeal leukemia in complete remission. After intraventricular injection of 30 mg Ara-C, CSF and plasma samples were obtained over a 24-hr period. Ara-C levels were measured by a reverse-phase HPLC assay (with a sensitivity of 0.5 microM in CSF and 1.0 microM in plasma) that readily separated Ara-C from its major metabolite uracil arabinoside (Ara-U). Elimination of Ara-C from CSF followed a biphasic pattern, with an initial t1/2 of 1 hr and a terminal t1/2 of 3.4 hr. Ara-C clearance from CSF was 0.42 ml/min, suggesting that drug elimination was primarily by CSF bulk flow. The ratio of the AUC of Ara-U to the AUC of Ara-C was 0.08, indicating only minor metabolism of Ara-C to Ara-U in CSF, in contrast to that after systemic Ara-C. Despite initial CSF Ara-C concentrations exceeding 2 mM, Ara-C was not detectable in plasma in any patient. Intraventricular Ara-C results in very high levels in CSF, but systemic tissues are relatively spared from exposure to Ara-C.

Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine

“…Intrathecal administration of DepoCyte results in peak free ara-C concentrations of 300 µM that decay with a half-life of 144 hours (Kim et al, 1993). This is in contrast to a CSF half-life of 3.4 hours for free unencapsulated ara-C (Zimm et al, 1984), and a CSF half-life of 4.5-8 hours for methotrexate (Shapiro et al, 1975;Bleyer and Dermick, 1977). Thus, it is reasonable to expect that DepoCyte should produce a response rate at least comparable to that of standard agents even when administered less frequently.…”

“…The particles eventually disappear from CSF and the lipids undergo degradation (Kohn et al, 1998). Whereas a single injection of free unencapsulated ara-C maintains cytotoxic concentrations in the CSF for <24 hours (Zimm et al, 1984), a single injection of 50 mg of DepoCyte maintains cytotoxic concentrations of ara-C in the CSF for >14 days in most patients, and the drug distribution within the neuraxis is relatively homogeneous (Kim et al, 1993). Thus, intrathecal administration of DepoCyte is required just once every 2 weeks as compared to a daily dose schedule which would theoretically be required to maintain cytotoxic concentrations in the CSF following injection of free unencapsulated ara-C.…”

Phase 2 study of intrathecal, long‐acting liposomal cytarabine in the prophylaxis of lymphomatous meningitis in human immunodeficiency virus‐related non‐Hodgkin lymphoma

“…Liposomal cytarabine, an encapsulated microvesicular liposome preparation, has shown significant activity in the treatment of lymphomatous meningitis, with a significant pharmacokinetic advantage in comparison with free cytarabine. A single injection of free cytarabine maintains cytotoxic concentrations in CSF for <24 hours, 48 whereas a single injection of 50 mg of liposomal cytarabine maintains cytotoxic concentrations of cytarabine in CSF for >14 days, and the drug is well distributed throughout the CSF. 49,50 All patients included into the study were considered at high risk of recurrence into the CNS because of underlying HIV infection, histology, elevated LDH, and involvement of particular extranodal sites.…”

Schedule-dependent synergism and antagonism between methotrexate and cytarabine against human leukemia cell lines in vitro

“…MTX and cytarabine are cell cycle-specific with short-half lives within the CSF. 44,45 As a result, the exposure of tumor cells in the CSF to the cytotoxic drug levels may be insufficient. Recently, a sustained-release formulating cytarabine capable (Depo-Cyto) of maintaining a cytotoxic concentration in the CSF for more than 14 days after a single injection has been incorporated into clinical use.…”