Glucarpidase to combat toxic levels of methotrexate in patients.

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Green JM

Glucarpidase to combat toxic levels of methotrexate in patients.

Ther Clin Risk Manag. 2012;8:403-13. doi: 10.2147/TCRM.S30135. Epub 2012 Nov 22.

PubMed ID

23209370 [ View in PubMed

]

Abstract

In January 2012, glucarpidase (Voraxaze((R))) received approval from the US Food and Drug Administration for intravenous treatment of toxic plasma methotrexate concentrations due to impaired renal clearance. Methotrexate, an antifolate agent, has been used for over 60 years in the treatment of various cancers. High-dose methotrexate has been particularly useful in the treatment of leukemias and lymphomas. However, even with aggressive hydration and urine alkalinization, such regimens can lead to acute renal dysfunction, as indicated by decreases in urine production and concomitant increases in blood urea nitrogen and serum creatinine levels. Because methotrexate is largely excreted by the kidneys, this can greatly potentiate tissue damage. Toxic levels of blood methotrexate can be rapidly and effectively decreased by intravenous administration of glucarpidase. Glucarpidase is a recombinant form of carboxypeptidase G2, a bacterial enzyme that rapidly cleaves methotrexate to form the amino acid glutamate and 2,4-diamino-N(10)-methylpteroic acid. Catabolites of methotrexate are much less toxic than the parent compound, and are primarily excreted by hepatic mechanisms. Glucarpidase has been available on a compassionate basis since the 1990s, and a variety of case reports and larger clinical trials have demonstrated the safety and efficacy of this drug in patients ranging in age from infants to the elderly and in a variety of races and ethnic groups. Glucarpidase should not be administered within 2 hours of leucovorin, because this agent is a reduced folate which competes with methotrexate for the enzyme and glucarpidase inactivates leucovorin. Side effects of glucarpidase are rare and relatively mild, and include paraesthesia, flushing, nausea, vomiting, pruritus, and headache. Glucarpidase has seen limited use in intrathecal treatment of methotrexate toxicity for which it is also effective. Future applications of this enzyme in chemotherapy continue to be an active area of research.

DrugBank Data that Cites this Article

Drugs

Glucarpidase

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Methotrexate	Carboxypeptidase G2	Protein	Pseudomonas sp. (strain RS-16)	Unknown	Substrate	Details

Drug Interactions

Drugs	Interaction
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Folic acid Glucarpidase	The serum concentration of the active metabolites of Folic acid can be reduced when Folic acid is used in combination with Glucarpidase resulting in a loss in efficacy.
Leucovorin Glucarpidase	The serum concentration of the active metabolites of Leucovorin can be reduced when Leucovorin is used in combination with Glucarpidase resulting in a loss in efficacy.
Levoleucovorin Glucarpidase	The serum concentration of the active metabolites of Levoleucovorin can be reduced when Levoleucovorin is used in combination with Glucarpidase resulting in a loss in efficacy.
Levomefolic acid Glucarpidase	The serum concentration of the active metabolites of Levomefolic acid can be reduced when Levomefolic acid is used in combination with Glucarpidase resulting in a loss in efficacy.
Methotrexate Glucarpidase	The serum concentration of the active metabolites of Methotrexate can be reduced when Methotrexate is used in combination with Glucarpidase resulting in a loss in efficacy.

Pharmaco-metabolomics

Drug	Drug Groups	Metabolite	Change	Description
Glucarpidase	Approved Investigational	Methotrexate	decreased	Glucarpidase decreases the level of Methotrexate in the blood