NITISINONE

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 Search

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
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21232lbl.pdf
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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
4-hydroxyphenylpyruvate dioxygenase 2 Target ID: CHEMBL1861 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9728330	Inhibitor 8504		5.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Hereditary tyrosinemia type 1 1 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21232lbl.pdf	Primary		Approved 8583	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

C_max

Value	Dose	Co-administered	Analyte	Population
7.69 μg/mL OTHER GOV'T https://www.tga.gov.au/sites/default/files/auspar-orfadin.pdf	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 DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209449s000lbl.pdf	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 OTHER GOV'T https://www.tga.gov.au/sites/default/files/auspar-orfadin.pdf	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 DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209449s000lbl.pdf	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
54.5 h OTHER GOV'T https://www.tga.gov.au/sites/default/files/auspar-orfadin.pdf	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 DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209449s000lbl.pdf	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

F_unbound

Value	Dose	Co-administered	Analyte	Population
5% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209449s000lbl.pdf	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

Dose	Population	Adverse events
80 mg single, oral Highest studied dose Dose: 80 mg Route: oral Route: single Dose: 80 mg Sources: https://pubmed.ncbi.nlm.nih.gov/30443705	healthy, 18-55 years Health Status: healthy Age Group: 18-55 years Sex: M+F Sources: https://pubmed.ncbi.nlm.nih.gov/30443705	Sources: https://pubmed.ncbi.nlm.nih.gov/30443705

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1946 inhibitor 2252	inhibitor 2438	inhibitor 2507

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2E1 1060 OAT1 725 OAT3 747 CYP1A2 2153 CYP2C19 2057 P-gp 1741 BCRP 910 OATP1B1 1079 OATP1B3 961 OCT2 779		CYP2E1 131 CYP1A2 832 CYP2B6 669 CYP3A4/5 133

Drug as perpetrator

Target	Modality	Activity
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/206356Orig1s000ClinPharmR.pdf Page: 14.0	inconclusive
CYP2E1 1146	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/206356Orig1s000ClinPharmR.pdf Page: 14.0	inconclusive
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/206356Orig1s000ClinPharmR.pdf Page: 14.0	likely
BCRP 985	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021232s023,206356s006lbl.pdf Page: 7.0	no
CYP1A2 2333	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021232s023,206356s006lbl.pdf Page: 7.0	no
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/206356Orig1s000ClinPharmR.pdf Page: 14.0	no
CYP2B6 1160	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021232s023,206356s006lbl.pdf Page: 7.0	no
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/206356Orig1s000ClinPharmR.pdf Page: 14.0	no
CYP3A4 2633	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/206356Orig1s000ClinPharmR.pdf Page: 14.0	no
CYP3A4/5 357	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021232s023,206356s006lbl.pdf Page: 7.0	no
OATP1B1 1095	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021232s023,206356s006lbl.pdf Page: 7.0	no
OATP1B3 970	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021232s023,206356s006lbl.pdf Page: 7.0	no
OCT2 782	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021232s023,206356s006lbl.pdf Page: 7.0	no
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021232s023,206356s006lbl.pdf Page: 7.0	no
CYP2E1 1146	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021232s023,206356s006lbl.pdf Page: 6.0	weak
OAT1 730	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021232s023,206356s006lbl.pdf Page: 6.0	yes
OAT3 749	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021232s023,206356s006lbl.pdf Page: 6.0	yes

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/206356Orig1s000ClinPharmR.pdf Page: 14.0	minor

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:50378	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:50378
ChemicalBook	CB61386686	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB61386686
eMolecules	10469657	https://www.emolecules.com/cgi-bin/more?vid=10469657
MolPort	MolPort-006-167-523	https://www.molport.com/shop/molecule-link/MolPort-006-167-523
ZINC	ZINC000100014475	http://zinc15.docking.org/substances/ZINC000100014475

PubMed

Title	Date	PubMed
Nitisinone. Ntbc, Orfadin.	2002	12001819
Corneal opacities associated with NTBC treatment.	2002 Aug	12140036
Natural history of alkaptonuria.	2002 Dec 26	12501223
From the Food and Drug Administration.	2002 Mar 6	11879090
Alkaptonuria.	2003 Apr 3	12672874
Interaction of (4-hydroxyphenyl)pyruvate dioxygenase with the specific inhibitor 2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione.	2003 Sep 2	12939152
Structure of the ferrous form of (4-hydroxyphenyl)pyruvate dioxygenase from Streptomyces avermitilis in complex with the therapeutic herbicide, NTBC.	2004 Jun 1	15157070
Transcriptome analysis of Paracoccidioides brasiliensis cells undergoing mycelium-to-yeast transition.	2005 Dec	16339729
Hepatomegaly: commentary.	2005 Nov-Dec	16327972
Kidneys of mice with hereditary tyrosinemia type I are extremely sensitive to cytotoxicity.	2006 Mar	16492973
Quantitative determination of succinylacetone in dried blood spots for newborn screening of tyrosinemia type I.	2006 May	16448836
Harnessing a high cargo-capacity transposon for genetic applications in vertebrates.	2006 Nov 10	17096595
[New drugs; nitisinone].	2006 Nov 18	17152330
Nitisinone: new drug. Type 1 tyrosinemia: an effective drug.	2007 Apr	17458044
Messenger RNA as a source of transposase for sleeping beauty transposon-mediated correction of hereditary tyrosinemia type I.	2007 Jul	17440442
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	19039335
Activation of nuclear factor E2-related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development.	2008 Aug	18666252
Severe neurological crisis in a patient with hereditary tyrosinaemia type I after interruption of NTBC treatment.	2008 Dec	18500574
NTBC treatment in tyrosinaemia type I: long-term outcome in French patients.	2008 Feb	18214711
Hepatic stress in hereditary tyrosinemia type 1 (HT1) activates the AKT survival pathway in the fah-/- knockout mice model.	2008 Feb	18093685
Loss of p21 permits carcinogenesis from chronically damaged liver and kidney epithelial cells despite unchecked apoptosis.	2008 Jul 8	18598944
Renal tubular function in children with tyrosinaemia type I treated with nitisinone.	2008 Jun	18509744
Rescue from neonatal death in the murine model of hereditary tyrosinemia by glutathione monoethylester and vitamin C treatment.	2008 Mar	18023223
Experience of nitisinone for the pharmacological treatment of hereditary tyrosinaemia type 1.	2008 May	18422479
Alkaptonuria diagnosed in a 4-month-old baby girl: a case report.	2008 Nov 13	19014543
Inhibition of 4-hydroxyphenylpyruvate dioxygenase by 2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione.	2009	19621095
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	19345648
[Clinical, biochemical and molecular characteristics in 11 Czech children with tyrosinemia type I].	2010	21117323
Persistent coagulopathy during Escherichia coli sepsis in a previously healthy infant revealed undiagnosed tyrosinaemia type 1.	2010 Dec 29	22802474
A metabolic cause of spinal deformity.	2010 Jan	19765774
Alkaptonuria.	2010 Nov 15	21163157
A late and difficult diagnosis of ochronosis.	2010 Oct-Dec	21254745

Patents

Sample Use Guides

In Vivo Use Guide

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

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

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Name

Type

Language

ORFADIN

Preferred Name

English

NITISINONE

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