U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS
This repository is under review for potential modification in compliance with Administration directives.

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
Structure of NITISINONE

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

HIDE SMILES / InChI

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

Description
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.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
5.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
ORFADIN

Approved Use

ORFADIN® 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 Date

2002
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
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

AUC

ValueDoseCo-administeredAnalytePopulation
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

T1/2

ValueDoseCo-administeredAnalytePopulation
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

Funbound

ValueDoseCo-administeredAnalytePopulation
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
Doses

Doses

DosePopulationAdverse events​
80 mg single, oral
Highest studied dose
Dose: 80 mg
Route: oral
Route: single
Dose: 80 mg
Sources:
healthy, 18-55 years
Health Status: healthy
Age Group: 18-55 years
Sex: M+F
Sources:
Overview

Overview

Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
inconclusive
inconclusive
likely
no
no
no
no
no
no
no
no
no
no
no
weak
yes
yes
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
minor
PubMed

PubMed

TitleDatePubMed
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
Patents

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
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 Mon Mar 31 18:04:59 GMT 2025
Edited
by admin
on Mon Mar 31 18:04:59 GMT 2025
Record UNII
K5BN214699
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
ORFADIN
Preferred Name English
NITISINONE
EMA EPAR   INN   JAN   MART.   MI   ORANGE BOOK   USAN   VANDF   WHO-DD  
INN   USAN  
Official Name English
NITISINONE [VANDF]
Common Name English
SC-0735
Code English
NITISINONE [JAN]
Common Name English
2-(.ALPHA.,.ALPHA.,.ALPHA.-TRIFLUORO-2-NITRO-P-TULUOYL)-1,3-CYCLOHEXANEDIONE
Common Name English
NITYR
Brand Name English
NITISINONE [MI]
Common Name English
NITISINONE [ORANGE BOOK]
Common Name English
Nitisinone [WHO-DD]
Common Name English
1,3-CYCLOHEXANEDIONE, 2-(2-NITRO-4-(TRIFLUOROMETHYL)BENZOYL)-
Systematic Name English
nitisinone [INN]
Common Name English
NITISINONE [MART.]
Common Name English
NTBC
Common Name English
NITISINONE [EMA EPAR]
Common Name English
NITISINONE [USAN]
Common Name English
Classification Tree Code System Code
WHO-VATC QA16AX04
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
EPA PESTICIDE CODE 12802
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
WHO-ATC A16AX04
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
NCI_THESAURUS C471
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
FDA ORPHAN DRUG 942723
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
FDA ORPHAN DRUG 148701
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
NDF-RT N0000175808
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
NDF-RT N0000175809
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
EU-Orphan Drug EU/3/00/012
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
FDA ORPHAN DRUG 89095
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
EMA ASSESSMENT REPORTS ORFADIN (AUTHORIZED: TYROSINEMIAS)
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
Code System Code Type Description
CAS
104206-65-7
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY
DRUG BANK
DB00348
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY
IUPHAR
6834
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY
JAPANESE REVIEW
ORFADIN
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY APPROVED DECEMBER 2014
RXCUI
61805
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY RxNorm
INN
7720
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY
WIKIPEDIA
Nitisinone
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY
CHEBI
50378
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY
SMS_ID
100000085452
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY
EPA CompTox
DTXSID9042673
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY
MERCK INDEX
m7926
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY Merck Index
MESH
C077073
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY
DRUG CENTRAL
1944
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY
DAILYMED
K5BN214699
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY
EVMPD
SUB09313MIG
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY
ChEMBL
CHEMBL1337
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY
USAN
OO-34
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY
FDA UNII
K5BN214699
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY
PUBCHEM
115355
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY
NCI_THESAURUS
C61862
Created by admin on Mon Mar 31 18:04:59 GMT 2025 , Edited by admin on Mon Mar 31 18:04:59 GMT 2025
PRIMARY
Related Record Type Details
BINDER->LIGAND
BINDING
TARGET -> INHIBITOR
Related Record Type Details
METABOLITE -> PARENT
IN-VIVO
URINE
METABOLITE -> PARENT
IN-VIVO
URINE
METABOLITE -> PARENT
IN-VIVO
URINE
Related Record Type Details
ACTIVE MOIETY
Name Property Type Amount Referenced Substance Defining Parameters References
Volume of Distribution PHARMACOKINETIC
Biological Half-life PHARMACOKINETIC
Tmax PHARMACOKINETIC administered as a capsule