Rescue of experimental intrathecal methotrexate overdose with carboxypeptidase-G2.
The carboxypeptidase G class of enzymes rapidly hydrolyze methotrexate (MTX) into the inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate. This study evaluated the use of carboxypeptidase-G2 (CPDG2) as a potential intrathecal (IT) rescue agent for massive IT MTX overdose. The CSF pharmacokinetics of MTX with and without CPDG2 rescue was studied in adult rhesus monkeys (Macaca mulatta) using a nontoxic IT 5 mg dose (equivalent to 50 mg in humans). Without CPDG2 rescue, peak CSF MTX concentration was 2,904 +/- 340 mumol/L. Within 5 minutes of administration of 30 U IT CPDG2, CSF MTX concentrations decreased greater than 400-fold to 6.55 +/- 6.7 microM. Subsequently, groups of three monkeys received either 25 mg IT MTX (equivalent to 250 mg in humans) followed by 150 U IT CPDG2 or 50 mg IT MTX (equivalent to 500 mg in humans) followed by 300 U IT CPDG2. All animals survived without neurotoxicity. Our studies suggest that CPDG2 may prove to be an important addition to the currently recommended strategy for the management of IT MTX overdose.
Adamson
P C
PC
Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Balis
F M
FM
McCully
C L
CL
Godwin
K S
KS
Bacher
J D
JD
Walsh
T J
TJ
Poplack
D G
DG
D000818:Animals; D062787:Drug Overdose / Q000188:drug therapy; D007278:Injections, Spinal; D008253:Macaca mulatta; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000506:poisoning*; D011623:gamma-Glutamyl Hydrolase / Q000627:therapeutic use*
D011623:gamma-Glutamyl Hydrolase; D008727:Methotrexate