Details
Stereochemistry | ACHIRAL |
Molecular Formula | C14H10F3NO5 |
Molecular Weight | 329.2281 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
[O-][N+](=O)C1=CC(=CC=C1C(=O)C2C(=O)CCCC2=O)C(F)(F)F
InChI
InChIKey=OUBCNLGXQFSTLU-UHFFFAOYSA-N
InChI=1S/C14H10F3NO5/c15-14(16,17)7-4-5-8(9(6-7)18(22)23)13(21)12-10(19)2-1-3-11(12)20/h4-6,12H,1-3H2
Molecular Formula | C14H10F3NO5 |
Molecular Weight | 329.2281 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
DescriptionCurator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/25266991
https://www.ncbi.nlm.nih.gov/pubmed/25266991
Curator's Comment: Description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/pubmed/25266991
https://www.ncbi.nlm.nih.gov/pubmed/25266991
Nitisinone, 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) is a triketone with herbicidal activity. Orfadin® capsules contain nitisinone used in the treatment of hereditary tyrosinemia type 1 (HT-1). Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme
upstream of fumarylacetoacetase in the tyrosine catabolic pathway. By inhibiting the normal
catabolism of tyrosine in patients with HT-1, nitisinone prevents the accumulation of the
catabolic intermediates maleylacetoacetate and fumarylacetoacetate. In patients with HT-1,
these catabolic intermediates are converted to the toxic metabolites succinylacetone and
succinylacetoacetate, which are responsible for the observed liver and kidney toxicity.
Succinylacetone can also inhibit the porphyrin synthesis pathway leading to the accumulation
of 5-aminolevulinate, a neurotoxin responsible for the porphyric crises characteristic of HT-1. Zeneca Agrochemicals and Zeneca Pharmaceuticals made NTBC available for clinical use and, with the approval of the Swedish Medical Products Agency, a seriously ill child with an acute form of tyrosinaemia type 1 was successfully treated in February 1991.
Nitisinone is investigated as a potential treatment for other disorders of tyrosine metabolism including alkaptonuria.
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL1861 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9728330 |
5.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | ORFADIN Approved UseORFADIN® capsules (nitisinone) are indicated as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of patients with hereditary tyrosinemia type 1 (HT-1). ORFADIN is a synthetic reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase indicated for use as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 (HT-1). (1) Launch Date2002 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
7.69 μg/mL |
1 mg/kg single, oral dose: 1 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
NITISINONE plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
1278 ng/mL |
10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered: |
NITISINONE plasma | Homo sapiens population: HEALTHY age: UNKNOWN sex: UNKNOWN food status: FASTED |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
599 μg × h/mL |
1 mg/kg single, oral dose: 1 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
NITISINONE plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
77874 ng × h/mL |
10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered: |
NITISINONE plasma | Homo sapiens population: HEALTHY age: UNKNOWN sex: UNKNOWN food status: FASTED |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
54.5 h |
1 mg/kg single, oral dose: 1 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
NITISINONE plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
59.3 h |
10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered: |
NITISINONE plasma | Homo sapiens population: HEALTHY age: UNKNOWN sex: UNKNOWN food status: FASTED |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
5% |
10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered: |
NITISINONE plasma | Homo sapiens population: HEALTHY age: UNKNOWN sex: UNKNOWN food status: FASTED |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 14.0 |
inconclusive | |||
Page: 14.0 |
inconclusive | |||
Page: 14.0 |
likely | |||
Page: 7.0 |
no | |||
Page: 7.0 |
no | |||
Page: 14.0 |
no | |||
Page: 7.0 |
no | |||
Page: 14.0 |
no | |||
Page: 14.0 |
no | |||
Page: 7.0 |
no | |||
Page: 7.0 |
no | |||
Page: 7.0 |
no | |||
Page: 7.0 |
no | |||
Page: 7.0 |
no | |||
Page: 6.0 |
weak | |||
Page: 6.0 |
yes | |||
Page: 6.0 |
yes |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 14.0 |
minor |
PubMed
Title | Date | PubMed |
---|---|---|
Nitisinone. Ntbc, Orfadin. | 2002 |
|
Corneal opacities associated with NTBC treatment. | 2002 Aug |
|
Natural history of alkaptonuria. | 2002 Dec 26 |
|
From the Food and Drug Administration. | 2002 Mar 6 |
|
Alkaptonuria. | 2003 Apr 3 |
|
Interaction of (4-hydroxyphenyl)pyruvate dioxygenase with the specific inhibitor 2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione. | 2003 Sep 2 |
|
Structure of the ferrous form of (4-hydroxyphenyl)pyruvate dioxygenase from Streptomyces avermitilis in complex with the therapeutic herbicide, NTBC. | 2004 Jun 1 |
|
Transcriptome analysis of Paracoccidioides brasiliensis cells undergoing mycelium-to-yeast transition. | 2005 Dec |
|
Hepatomegaly: commentary. | 2005 Nov-Dec |
|
Kidneys of mice with hereditary tyrosinemia type I are extremely sensitive to cytotoxicity. | 2006 Mar |
|
Quantitative determination of succinylacetone in dried blood spots for newborn screening of tyrosinemia type I. | 2006 May |
|
Harnessing a high cargo-capacity transposon for genetic applications in vertebrates. | 2006 Nov 10 |
|
[New drugs; nitisinone]. | 2006 Nov 18 |
|
Nitisinone: new drug. Type 1 tyrosinemia: an effective drug. | 2007 Apr |
|
Messenger RNA as a source of transposase for sleeping beauty transposon-mediated correction of hereditary tyrosinemia type I. | 2007 Jul |
|
Identification of 2-[2-nitro-4-(trifluoromethyl)benzoyl]- cyclohexane-1,3-dione metabolites in urine of patients suffering from tyrosinemia type I with the use of 1H and 19F NMR spectroscopy. | 2008 |
|
Activation of nuclear factor E2-related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development. | 2008 Aug |
|
Severe neurological crisis in a patient with hereditary tyrosinaemia type I after interruption of NTBC treatment. | 2008 Dec |
|
NTBC treatment in tyrosinaemia type I: long-term outcome in French patients. | 2008 Feb |
|
Hepatic stress in hereditary tyrosinemia type 1 (HT1) activates the AKT survival pathway in the fah-/- knockout mice model. | 2008 Feb |
|
Loss of p21 permits carcinogenesis from chronically damaged liver and kidney epithelial cells despite unchecked apoptosis. | 2008 Jul 8 |
|
Renal tubular function in children with tyrosinaemia type I treated with nitisinone. | 2008 Jun |
|
Rescue from neonatal death in the murine model of hereditary tyrosinemia by glutathione monoethylester and vitamin C treatment. | 2008 Mar |
|
Experience of nitisinone for the pharmacological treatment of hereditary tyrosinaemia type 1. | 2008 May |
|
Alkaptonuria diagnosed in a 4-month-old baby girl: a case report. | 2008 Nov 13 |
|
Inhibition of 4-hydroxyphenylpyruvate dioxygenase by 2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione. | 2009 |
|
Liquid chromatography tandem mass spectrometry method for the quantitation of NTBC (2-(nitro-4-trifluoromethylbenzoyl)1,3-cyclohexanedione) in plasma of tyrosinemia type 1 patients. | 2009 May 15 |
|
[Clinical, biochemical and molecular characteristics in 11 Czech children with tyrosinemia type I]. | 2010 |
|
Persistent coagulopathy during Escherichia coli sepsis in a previously healthy infant revealed undiagnosed tyrosinaemia type 1. | 2010 Dec 29 |
|
A metabolic cause of spinal deformity. | 2010 Jan |
|
Alkaptonuria. | 2010 Nov 15 |
|
A late and difficult diagnosis of ochronosis. | 2010 Oct-Dec |
Sample Use Guides
Treatment with nitisinone should be initiated by a physician experienced in the treatment of hereditary tyrosinemia type 1. The dose of nitisinone should be adjusted in each patient. The recommended initial dose is 1 mg/kg/day divided for morning and evening administration. Since an effect of food is unknown, nitisinone should be taken at least one hour before a meal. Because of the long halflife of nitisinone, the total dose may be split unevenly as convenient in order to limit the total number of capsules given at each administration. A nutritionist skilled in managing children with inborn errors of metabolism should be employed to design a low-protein diet deficient in tyrosine and phenylalanine. For young children, capsules may be opened and the contents suspended in a small amount of water, formula, or apple sauce immediately before use.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26024586
There is currently no literature surrounding the use of nitisinone in human in vitro models, or its effect on chondrocytes or osteoblast like cells. Nitisinone (1nM - uM) does not appear detrimental to cell viability of chondrocytes or osteoblast-like cells.
Substance Class |
Chemical
Created
by
admin
on
Edited
Mon Mar 31 18:04:59 GMT 2025
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on
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Record UNII |
K5BN214699
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Record Status |
Validated (UNII)
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Record Version |
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WHO-VATC |
QA16AX04
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EPA PESTICIDE CODE |
12802
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WHO-ATC |
A16AX04
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NCI_THESAURUS |
C471
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FDA ORPHAN DRUG |
942723
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FDA ORPHAN DRUG |
148701
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NDF-RT |
N0000175808
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NDF-RT |
N0000175809
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EU-Orphan Drug |
EU/3/00/012
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FDA ORPHAN DRUG |
89095
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EMA ASSESSMENT REPORTS |
ORFADIN (AUTHORIZED: TYROSINEMIAS)
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DB00348
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ORFADIN
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61805
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Nitisinone
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m7926
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METABOLITE -> PARENT |
IN-VIVO
URINE
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ACTIVE MOIETY |
Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Volume of Distribution | PHARMACOKINETIC |
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Biological Half-life | PHARMACOKINETIC |
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Tmax | PHARMACOKINETIC |
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administered as a capsule |
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