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Glucarpidase (carboxypeptidase G2, CPDG2) is indicated for the manage­ment of methotrexate (MTX) toxicity. When given intravenously or intrathecally, it rapidly enzymatically inactivates MTX, folates and folate analogues. It does not substitute for and must be used in conjunction with leucovorin (Antidotes in Depth: A10). Leucovorin should not be administered within two hours before or after a dose of glucarpidase.


Soon after the description of the structure and synthesis of folate,6 a Flavobacterium species capable of removing the glutamate moiety of folate was discovered.37 From 1955 to 1956, the inactivation of folate analogues (including by the chemotherapeutic aminopterin) was demonstrated in bacteria and yeasts.51,72 Purification of “carboxypeptidase G,” a pseudomonad-­derived, zinc-dependent enzyme responsible for MTX cleavage, was reported in 1967.28,38 Other bacterial carboxypeptidases that differed in their substrate specificity and kinetics were isolated and purified in 1971 (Pseudomonas stutzeri carboxypeptidase G1),431978 (Flavobacterium carboxypeptidase),5 and 1992 (Pseudomonas spp M-27 carboxypeptidase G3).80 By 1976, carboxypeptidase G1 was scaled to pilot manufacturing production.18 Carboxypeptidase G1 was initially explored as a chemotherapeutic to deprive growing tumors of folate.8,9,15,34 Human usage of CPDG1 for this purpose was reported in 1974.9 The antidotal potential of carboxypeptidase was first suggested in 1972 when it was noted that carboxypeptidase G1 rapidly decreased MTX concentrations and improved survival in mice injected with lethal MTX doses.16 CPDG1 was subsequently used to selectively eliminate systemic MTX in patients treated with high dosages targeting central nervous system (CNS) malignancies.1,2 CPDG1 was first used for rescue in a patient receiving MTX with kidney failure in 1978.32 Unfortunately, the enzyme source of CPDG1 was then lost.4,82 The carboxypeptidase currently used in clinical practice (carboxypeptidase G2) was cloned from Pseudomonas strain R16 and sequenced, characterized, and expressed in Escherichia coli in the early 1980s.46, 47, and 48,63 The preliminary crystal structure was provided in 1991, with a complete characterization (at 2.5 Å) and description of the active site and biochemical mechanism of action in 1997.39,59,69 After the renewed availability of the recombinant CPDG2 product, it underwent nonhuman primate testing for both intravenous (IV) and intrathecal (IT) rescue of MTX overdose.3,4 Reports of successful use in human IV and IT MTX overdose rapidly emerged.7,14,19,21,29,32,35,36,40,49,52,53,56,60,62,64,66,67,71,74,76, 77, and 78,82 The US Food and Drug Administration designated glucarpidase an orphan product in 2003 and ...

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