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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 intravascular or intrathecal MTX, respectively as well as folates and folate analogues. It is not a substitute for and must be used in conjunction with leucovorin (see Antidotes in Depth A13: Leucovorin [Folinic Acid] and Folic Acid). In most cases glucarpidase administration should precede or follow the use of leucovorin by at least 2 to 4 hours, unless a carefully considered benefit-risk analysis suggests the need to more rapidly eliminate MTX and risk leucovorin inactivation.

Soon after the discovery of the structure and synthesis of folate,7 a Flavobacterium species capable of removing the glutamate moiety of folate was described.34 This was followed by additional reports of Bacillus species with glutamyl peptidase activity.33,68 From 1955 to 1996 a series of experiments demonstrated the inactivation of folate analogues (including chemotherapeutic aminopterin) by bacteria and yeasts.49,74 Other bacteria with similar folate glutamate-cleaving ability were later identified.41,56,72 In 1967 purification of "carboxypeptidase G," a pseudomonad derived zinc-dependent enzyme responsible for MTX cleavage, was reported.25,35 Carboxypeptidases from other bacterial species which differed in their substrate specificity and kinetics were later isolated and purified in 1971 (Pseudomonas stutzeri carboxypeptidase G1),40 1978 (Flavobacterium carboxypeptidase),6 and 1992 (Pseudomonas sp. M-27 carboxypeptidase G3).82 By 1976 carboxypeptidase G1 was scaled to pilot manufacturing production.17 The carboxypeptidase currently used in clinical practice (carboxypeptidase G2) was cloned from Pseudomonas strain R-16 and sequenced, characterized, and expressed in Escherichia coli in the early 1980s.44-46,63 A preliminary crystal structure was provided in 1991, with a complete characterization (at 2.5 Å), description of the active site, and biochemical mechanism of action was presented in 1997.36,58,70

Carboxypeptidase G1 was initially explored as an anticancer agent because of its ability to deprive growing tumors of folate.9,10,15,30 Human usage of CPDG1 for this purpose was reported in 1974.10 The antidotal potential of carboxypeptidase was suggested in 1972—carboxypeptidase G1 rapidly decreased MTX levels 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) malignancy.1,2 CPDG1 was first used for rescue in a patient receiving MTX with renal failure in 1978.28 Unfortunately, the enzyme source of CPDG1 was then lost.5,84 Following the revival of the recombinant CPDG2 product, it underwent nonhuman primate testing for both intravenous (IV) and intrathecal (IT) rescue for MTX overdose.4,5 Reports of successful use in human IV and IT MTX overdose rapidly emerged.8,14,18,20,26,28,31,32,37,47,50,51,53,59-62,64,66,...

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