Abstract

Asparaginase (ASNase) is used to treat various hematological malignancies for its capacity to deplete asparagine (ASN) in serum and cerebrospinal fluid (CSF). Since the biological mechanisms underlying CSF asparagine depletion in humans are not yet fully elucidated, this study compared, for the first time, the pharmacological properties of three clinically used ASNase formulations in a rodent model. Male Wistar rats were treated with E.coli-ASNase, PEG-ASNase, or ERW-ASNase at different doses. Serum and CSF amino-acid levels and ASNase activities were evaluated at 1 and 24h after the intravenous administration of different ASNase doses. All the ASNase formulations showed higher activities in serum after 1h than 24h and completely deplete ASN. Mean ASNase activity in the CSF at 1h was higher with ERW-ASNase compared to PEG-ASNase (36±29 vs 8±7U/L, p<0.037) and similar to E.coli-ASNase (21±9U/L, ns). ERW-ASNase and E.coli-ASNase at the highest doses were able to deplete ASN in the CSF after 1h. This effect was transient and not evident at 24h after treatment. Together with the ASN depletion in serum and CSF, a never before demonstrated transient penetration of ASNases into the CSF, more evident for non-pegylated formulations, was detected when the ASNases were administered at high dose.

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