L-Asparaginase Pharmacokinetics and Asparagine Levels in Cerebrospinal Fluid of Rhesus Monkeys and Humans1

L-Asparaginase has been widely used for the treatment of acute lymphoblastic leukemia. Therapeutic and toxic effects in the central nervous system have been noted with systemic treatment. In order to better define the relationship between L-asparaginase administration and cerebrospinal fluid (CSF) asparagine levels, L-asparaginase and asparagine were mea sured in the CSF of rhesus monkeys following intrathecal and i.v. administration. Following intrathecal injection, the enzyme activity of Escherichia coli L-asparaginase in the CSF demonstrated a more rapid terminal half-life than did that of '"In-labeled diethylenetriaminepentaacetic acid, a marker of CSF bulk flow [4 ± 0.7 (S.D.) hr versus 5.8 ±0.2 hr]. Intrathecal injection of E. coli asparaginase resulted in complete depletion of CSF as paragine for at least 5 days. A similar period of CSF asparagine depletion was observed following i.v. administration of L-as paraginase. Similar results were found in seven patients un dergoing systemic L-asparaginase therapy. The minimal plasma level of L-asparaginase necessary to deplete CSF as paragine in both species was 0.1 Ill/ml. Two other enzymes, Erwinia L-asparaginase and succinylated Acinetobacter glutaminase-asparaginase, were cleared from the CSF at the same rate as bulk flow. These data indicate that systemic L-asparaginase therapy may be a feasible means of treating central nervous system involvement in patients with acute lymphoblastic leukemia and that there is no therapeutic advantage to using intrathecal L-