Glucarpidase

Identification

Summary

Glucarpidase is a carboxypeptidase enzyme used to treat toxic plasma methotrexate concentrations by providing an alternate elimination pathway for methotrexate in patients who have impaired renal function.

Brand Names
Voraxaze
Generic Name
Glucarpidase
DrugBank Accession Number
DB08898
Background

Glucarpidase is the recombinant form of the Pseudomonas sp. (strain RS-16) enzyme carboxypeptidase G2 that is produced in Escherichia coli. In patients, glucarpidase inactivates methotrexate, and other antifolates, by hydrolyzing glutamate on the carboxyl terminal of these compounds. Therefore since methotrexate is eliminated enzymatically and not by the kidneys, glucarpidase is indicated in patients on methotrexate treatment who have kidney dysfunction, and are experiencing an abnormally high plasma concentration of methotrexate (>1 micromole per liter). Glucarpidase is marketed under the brand name Voraxaze®.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Recombinant Enzymes
Protein Structure
Db08898
Protein Chemical Formula
C1950H3157N543O599S7
Protein Average Weight
44016.6653 Da
Sequences
> Glucarpidase
ALAQKRDNVLFQAATDEQPAVIKTLEKLVNIETGTGDAEGIAAAGNFLEAELKNLGFTVT
RSKSAGLVVGDNIVGKIKGRGGKNLLLMSHMDTVYLKGILAKAPFRVEGDKAYGPGIADD
KGGNAVILHTLKLLKEYGVRDYGTITVLFNTDEEKGSFGSRDLIQEEAKLADYVLSFEPT
SAGDEKLSLGTSGIAYVQVNITGKASHAGAAPELGVNALVEASDLVLRTMNIDDKAKNLR
FNWTIAKAGNVSNIIPASATLNADVRYARNEDFDAAMKTLEERAQQKKLPEADVKVIVTR
GRPAFNAGEGGKKLVDKAVAYYKEAGGTLGVEERTGGGTDAAYAALSGKPVIESLGLPGF
GYHSDKAEYVDISAIPRRLYMAARLIMDLGAGK
Download FASTA Format
Synonyms
  • Carboxypeptidase G2
  • Folate hydrolase G2
  • Glucarpidase
  • Glutamate carboxypeptidase
  • Pteroylmonoglutamic acid hydrolase G2

Pharmacology

Indication

Used in patients on methotrexate treatment who have kidney dysfunction, and are experiencing an abnormally high plasma concentration of methotrexate (> 1 micromole per liter).

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Glucarpidase acts as an antidote to toxic methotrexate levels by elminating methotrexate by a non-kidney route.

Mechanism of action

Glucarpidase inactivates methotrexate, and other antifolates, by hydrolyzing glutamate on the carboxyl terminal of these compounds. For methotrexate specifically, it is hydrolyzed to the inactive metabolites glutamate and 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA).

TargetActionsOrganism
AMethotrexate
metabolizer
Humans
Absorption

In healthy patients not taking methotrexate, the average maximum concentration for glucarpidase was 3.3 μg/mL.

Volume of distribution

Glucarpidase is likely limited to the plasma volume since its volume of distribution is 3.6 L.

Protein binding

Plasma protein binding was not quantified.

Metabolism

Metabolism was not determined.

Route of elimination

Route of elmination was not determined.

Half-life

In healthy patients not taking methotrexate, glucarpidase has an elimination half-life of 5.6 hours. In patients with severe renal impairment (creatinine clearance <30 mL/min), glucarpidase has an longer elimination half-life at 8.2 hours.

Clearance

In healthy patients not taking methotrexate, glucarpidase has a clearance of 7.5 mL/min.

Adverse Effects
Medicalerrors
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Toxicity

Most common adverse reactions include hypotension, flushing, nausea, vomiting, headache, and paresthesia.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

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.
DrugInteraction
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 metabolism of Methotrexate can be increased when combined with Glucarpidase.
PemetrexedThe metabolism of Pemetrexed can be increased when combined with Glucarpidase.
PralatrexateThe metabolism of Pralatrexate can be increased when combined with Glucarpidase.
RaltitrexedThe metabolism of Raltitrexed can be increased when combined with Glucarpidase.
Interactions
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Food Interactions
  • Take with or without food.

Products

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

Categories

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

Chemical Identifiers

UNII
2GFP9BJD79
CAS number
9074-87-7

References

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]
UniProt
P06621
KEGG Drug
D10260
PubChem Substance
347910382
RxNav
1242127
ChEMBL
CHEMBL1863515
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Glucarpidase
FDA label
Download (367 KB)
MSDS
Download (83.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAcute Lymphoblastic Leukaemias (ALL)1
2CompletedTreatmentNeoplasms1
2RecruitingTreatmentMalignant Lymphomas1
2TerminatedTreatmentSarcoma, Osteogenic1
2TerminatedTreatmentSarcoma, Osteogenic / Spindle Cell Sarcoma of Bone1
1CompletedTreatmentKidney Diseases1
1CompletedTreatmentLeukemias / Malignant Lymphomas / Sarcoma, Osteogenic1
1, 2CompletedTreatmentChemotherapeutic Agent Toxicity / Malignant Lymphomas / Mucositis / Neurologic toxicity1
1, 2RecruitingTreatmentCentral Nervous System Lymphoma1
1, 2TerminatedSupportive CareMalignancies, Hematologic / Tumors, Solid1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous1000 [USP'U]/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Targets

Drugtargets
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Kind
Small molecule
Organism
Humans
Pharmacological action
Yes
Actions
Metabolizer
References
  1. Buchen S, Ngampolo D, Melton RG, Hasan C, Zoubek A, Henze G, Bode U, Fleischhack G: Carboxypeptidase G2 rescue in patients with methotrexate intoxication and renal failure. Br J Cancer. 2005 Feb 14;92(3):480-7. [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. 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]

Drug created on June 05, 2013 04:24 / Updated on February 21, 2021 18:52