Glucarpidase

Identification

Name
Glucarpidase
Accession Number
DB08898
Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Recombinant Enzymes
Description

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®.

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
  • Glutamate carboxypeptidase
  • Pteroylmonoglutamic acid hydrolase G2
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
VoraxazeInjection, powder, for solution1000 [USP'U]/1IntravenousBtg International Inc2012-04-01Not applicableUs
Categories
UNII
2GFP9BJD79
CAS number
9074-87-7

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).

Structured Indications
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
Human
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.

Toxicity

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

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
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.Approved
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.Approved
Food Interactions
  • No food effects were found.

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. [PubMed:23209370]
  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. [PubMed:23170306]
External Links
UniProt
P06621
KEGG Drug
D10260
ChEMBL
CHEMBL1863515
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Glucarpidase
ATC Codes
V03AF09 — Glucarpidase
FDA label
Download (367 KB)
MSDS
Download (83.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentChemotherapeutic Agent Toxicity / Malignant Lymphomas / Mucositis / Neurotoxicity1
1, 2TerminatedSupportive CareMalignancies, Hematologic / Tumors, Solid1
2CompletedTreatmentNeoplasms1
2TerminatedTreatmentSarcoma, Osteogenic1
2TerminatedTreatmentSarcoma, Osteogenic / Spindle Cell Sarcoma of Bone1
3CompletedTreatmentAcute Lymphoblastic Leukaemias (ALL) / Acute Lymphocytic Leukemia (ALL)1
Not AvailableApproved for MarketingNot AvailableNeoplasms1
Not AvailableCompletedSupportive CareNeurotoxicity / Unspecified Adult Solid Tumor, Protocol Specific / Unspecified Childhood Solid Tumor, Protocol Specific1

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

Taxonomy

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

Targets

Kind
Small molecule
Organism
Human
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. [PubMed:15668713]
  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. [PubMed:23170306]
  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. [PubMed:23209370]

Drug created on June 04, 2013 22:24 / Updated on August 17, 2016 12:24