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=C(C=CC(=C1)C(F)(F)F)C(=O)C2C(=O)CCCC2=O
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 Date1.01131197E12 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
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 |
---|---|---|---|---|
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 |
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 |
|
The role of mode of action studies in extrapolating to human risks in toxicology. | 2003 Apr 11 |
|
4-Hydroxyphenylpyruvate dioxygenase as a drug discovery target. | 2003 Oct |
|
Liquid chromatography-tandem mass spectrometry method for the simultaneous determination of delta-ALA, tyrosine and creatinine in biological fluids. | 2004 Dec |
|
Alkaptonuric ochronosis with aortic valve and joint replacements and femoral fracture: a case report and literature review. | 2004 Nov |
|
Renal proximal tubular cells acquire resistance to cell death stimuli in mice with hereditary tyrosinemia type 1. | 2004 Sep |
|
D-serine-induced nephrotoxicity: possible interaction with tyrosine metabolism. | 2004 Sep 1 |
|
Transcriptome analysis of Paracoccidioides brasiliensis cells undergoing mycelium-to-yeast transition. | 2005 Dec |
|
Drug discovery from medicinal plants. | 2005 Dec 22 |
|
Spectroscopic and computational studies of NTBC bound to the non-heme iron enzyme (4-hydroxyphenyl)pyruvate dioxygenase: active site contributions to drug inhibition. | 2005 Dec 9 |
|
Use of nitisinone in patients with alkaptonuria. | 2005 Jun |
|
New developments in ochronosis: review of the literature. | 2005 Mar |
|
Response of metastatic recurrent neuroblastoma to nitisinone: a modulator of tyrosine metabolism. | 2006 Apr |
|
Cardiomyopathy in tyrosinaemia type I is common but usually benign. | 2006 Feb |
|
Quantitative determination of succinylacetone in dried blood spots for newborn screening of tyrosinemia type I. | 2006 May |
|
In silico prediction of pregnane X receptor activators by machine learning approaches. | 2007 Jan |
|
Hepatic stress in hereditary tyrosinemia type 1 (HT1) activates the AKT survival pathway in the fah-/- knockout mice model. | 2008 Feb |
|
Rescue from neonatal death in the murine model of hereditary tyrosinemia by glutathione monoethylester and vitamin C treatment. | 2008 Mar |
|
No difference in between-country variability in use of newly approved orphan and non- orphan medicinal products--a pilot study. | 2009 Dec 14 |
|
Ochronosis as an unusual cause of valvular defect: a case report. | 2009 Nov 27 |
|
[Clinical, biochemical and molecular characteristics in 11 Czech children with tyrosinemia type I]. | 2010 |
|
Tyrosinemia type 1: metastatic hepatoblastoma with a favorable outcome. | 2010 Jul |
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
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Fri Dec 15 15:40:20 UTC 2023
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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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Code System | Code | Type | Description | ||
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104206-65-7
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DB00348
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6834
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ORFADIN
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PRIMARY | APPROVED DECEMBER 2014 | ||
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61805
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7720
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Nitisinone
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50378
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100000085452
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DTXSID9042673
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m7926
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C077073
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1944
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K5BN214699
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SUB09313MIG
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CHEMBL1337
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OO-34
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K5BN214699
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C61862
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BINDER->LIGAND |
BINDING
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TARGET -> INHIBITOR |
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Related Record | Type | Details | ||
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METABOLITE -> PARENT |
IN-VIVO
URINE
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METABOLITE -> PARENT |
IN-VIVO
URINE
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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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