Glucarpidase is a carboxypeptidase enzyme used to reduce plasma concentrations of methotrexate in patients with impaired renal function.

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Generic Name
DrugBank Accession Number

Glucarpidase is a recombinant carboxypeptidase G2 produced by genetically modified Escherichia coli bacteria. It is a 390-amino acid homodimer protein.4 High-dose methotrexate, an antifolate agent, has been widely and safely used for many decades in treating various cancers; however, even with aggressive hydration, urine alkalinization, and leucovorin rescue, some patients still develop high-dose methotrexate-induced nephrotoxicity. This can lead to delayed renal clearance of methotrexate and elevated drug plasma levels, increasing the risk of methotrexate toxicity.1,2

After the discovery of certain bacteria with the capacity to inactivate folate analogs such as methotrexate, carboxypeptidase G was identified and Carboxypeptidase G1 was first isolated from Pseudomonas stutzeri in 1967. In 1983, the gene for carboxypeptidase G2, or glucarpidase, was derived from Pseudomonas sp. strain RS-16 to be cloned into Escherichia coli, allowing the enzyme to be produced in sufficient quantities for therapeutic purposes.3 Glucarpidase is an enzyme that can rapidly hydrolyze methotrexate into its nontoxic metabolites. It prevents methotrexate toxicity in patients with renal dysfunction who are undergoing high-dose methotrexate treatment, as it provides an alternative non-renal pathway for methotrexate elimination.4 Glucarpidase was first approved by the FDA in January 2012,1 followed by the European Commission's approval in January 2022.5 It is marketed as VORAXAZE.

Approved, Investigational
Biologic Classification
Protein Based Therapies
Recombinant Enzymes
Protein Structure
Protein Chemical Formula
Protein Average Weight
83000.0 Da
  1. KEGG DRUG: Glucarpidase [Link]
Download FASTA Format
  • Carboxypeptidase G2
  • Folate hydrolase G2
  • Glucarpidase
  • Glutamate carboxypeptidase
  • Pteroylmonoglutamic acid hydrolase G2



Glucarpidase is indicated to reduce toxic plasma methotrexate concentration (greater than 1 micromole per litre) in adult and pediatric patients with delayed methotrexate clearance (plasma methotrexate concentrations greater than 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered) due to impaired renal function.4 In the European prescribing information, glucarpidase is specified for use in adults and children aged 28 days and older.6

Glucarpidase is not recommended for use in patients who exhibit the expected clearance and expected plasma methotrexate concentration. Reducing plasma methotrexate concentration in these patients may result in subtherapeutic exposure to methotrexate.4

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Prophylaxis ofMethotrexate toxicity••••••••••••••••••••••• •••••• ••••••• ••••••••• •••••••••••••••• •••••••••••• ••••••••••••••••••
Prophylaxis ofMethotrexate toxicity••••••••••••••••••• •••••••••••• •••••••••• •••••••• ••••• •••••••••••••••••
Contraindications & Blackbox Warnings
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Glucarpidase acts as an antidote to toxic methotrexate levels by eliminating methotrexate by a non-kidney route. In one study, methotrexate concentration measured by a chromatographic method was reduced by more than 97% within 15 minutes in all 22 treatment-evaluable patients who received glucarpidase 50 Units/kg: this effect was maintained at a >95% reduction up to 8 days in 20 of the 22 patients.4 It reduced the circulating levels of methotrexate in pediatric and adult patients, as well as patients with delayed methotrexate elimination.3

Mechanism of action

Methotrexate is an anticancer agent widely used to treat various cancers: it is often used in higher doses in leukemias and lymphomas. As methotrexate and its metabolites are primarily excreted in the kidneys, patients with reduced renal function are at an elevated risk for increased drug exposure and methotrexate toxicity. Methotrexate itself can cause renal toxicity at high doses: methotrexate-induced renal damage can occur by precipitation of methotrexate and its breakdown products in the renal tubules, or from a direct toxic effect of the drug.1

Glucarpidase is a recombinant bacterial enzyme that hydrolyzes the carboxyl-terminal glutamate residue from folic acid and classical antifolates such as methotrexate. Glucarpidase converts methotrexate to its inactive metabolites glutamate and 2,4-diamino-N10-methylpteroic acid (DAMPA),4 which is a nontoxic metabolite. DAMPA is later excreted in urine or further metabolized by the liver into hydroxyl-DAMPA, DAMPA-glucuronide, and hydroxy-DAMPA-glucuronide.1 Glucarpidase provides an alternate non-renal pathway for methotrexate elimination in patients with renal dysfunction during high-dose methotrexate treatment.4


In healthy adults who received glucarpidase 50 units/kg, the mean Cmax was 3.3 μg/mL and the mean area under the curve (AUC0-INF) was 23.3 μg x h/mL.4

Volume of distribution

In healthy adults who received glucarpidase 50 units/kg, the mean volume of distribution (Vd) was 3.6 L. 4

Protein binding

There is limited information.


There is limited information.

Route of elimination

There is limited information.


Following intravenous administration of glucarpidase 50 units/kg in healthy adults, serum glucarpidase activity levels declined with a mean elimination half-life (t1/2) of 5.6 hours and serum total glucarpidase concentration declined with a mean elimination half-life of 9 hours. 4


The mean systemic clearance (CL) was 7.5 mL/min in healthy adults who received glucarpidase 50 units/kg.4

Adverse Effects
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There is limited information regarding the LD50 and overdose of glucarpidase.

Not Available
Pharmacogenomic Effects/ADRs
Not Available


Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Folic acidThe 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.
LeucovorinThe 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.
LevoleucovorinThe 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 acidThe 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.
MethotrexateThe 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.
Food Interactions
No interactions found.


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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
VoraxazeInjection, powder, for solution1000 IU/mlIntravenousSerb Sas2022-05-04Not applicableEU flag
VoraxazeInjection, powder, for solution1000 [USP'U]/1IntravenousBTG International Inc.2012-04-01Not applicableUS flag


ATC Codes
V03AF09 — Glucarpidase
Drug Categories
Chemical TaxonomyProvided by Classyfire
Not Available
Organic Compounds
Super Class
Organic Acids
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Alternative Parents
Not Available
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

CAS number


General References
  1. 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. [Article]
  2. Tuffaha HW, Al Omar S: Glucarpidase for the treatment of life-threatening methotrexate overdose. Drugs Today (Barc). 2012 Nov;48(11):705-11. doi: 10.1358/dot.2012.48.11.1871575. [Article]
  3. Schwartz S, Borner K, Muller K, Martus P, Fischer L, Korfel A, Auton T, Thiel E: Glucarpidase (carboxypeptidase g2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy. Oncologist. 2007 Nov;12(11):1299-308. doi: 10.1634/theoncologist.12-11-1299. [Article]
  4. FDA Approved Drug Products: VORAXAZE (glucarpidase) for injection, for intravenous use [Link]
  5. GlobeNewswire: SERB receives EU approval for Voraxaze® (glucarpidase) as Rescue Therapy for High Dose Methotrexate Toxicity [Link]
  6. Summary of Product Characteristics: Voraxaze (glucarpidase) intravenous injection [Link]
PubChem Substance
RxList Drug Page Drug Page
FDA label
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Clinical Trials

Clinical Trials
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PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
3CompletedTreatmentAcute Lymphoblastic Leukemia (ALL)1somestatusstop reasonjust information to hide
2CompletedTreatmentNeoplasm1somestatusstop reasonjust information to hide
2SuspendedTreatmentLymphoma1somestatusstop reasonjust information to hide
2TerminatedTreatmentDiffuse Large B-Cell Lymphoma (DLBCL) / Therapeutic Agent Toxicity1somestatusstop reasonjust information to hide
2TerminatedTreatmentOsteosarcoma1somestatusstop reasonjust information to hide


Not Available
Not Available
Dosage Forms
Injection, powder, for solutionIntravenous1000 IU/ml
Injection, powder, for solutionIntravenous1000 [USP'U]/1
Powder, for solutionIntravenous1000 IU/ml
Not Available
Not Available


Experimental Properties
Not Available

Drug created at June 05, 2013 04:24 / Updated at January 27, 2022 21:15