Nitisinone

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Medication

title: "Nitisinone" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public tags: ["1-nitro-3-(trifluoromethyl)benzene-derivatives", "herbicides", "orphan-drugs", "aromatic-ketones"] description: "Medication" topic_path: "general/1-nitro-3-trifluoromethyl-benzene-derivatives" source: "https://en.wikipedia.org/wiki/Nitisinone" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Medication ::

::data[format=table title="Infobox drug"]

FieldValue
imageNitisinone.svg
image_classskin-invert-image
image2Nitisinone (ball-and-stick).png
image_class2bg-transparent
tradenameOrfadin, others
Drugs.com
DailyMedIDNitisinone
pregnancy_AU
routes_of_administrationBy mouth
ATC_prefixA16
ATC_suffixAX04
legal_AU
legal_BR
legal_CARx-only
legal_CA_comment
legal_DE
legal_NZ
legal_UK
legal_USRx-only
legal_US_comment
legal_EURx-only
legal_UN
legal_status
elimination_half-lifeApproximately 54 h (Range: 39 to 86 hours)
CAS_number_Ref
CAS_number104206-65-7
PubChem115355
IUPHAR_ligand6834
DrugBank_Ref
DrugBankDB00348
ChemSpiderID_Ref
ChemSpiderID103195
UNII_Ref
UNIIK5BN214699
KEGG_Ref
KEGGD05177
ChEBI_Ref
ChEBI50378
ChEMBL_Ref
ChEMBL1337
synonymsNTBC
IUPAC_name2-[2-nitro-4-(trifluoromethyl)benzoyl]
cyclohexane-1,3-dione
C14
H10
F3
N1
O5
SMILESO=C(c1ccc(cc1N+=O)C(F)(F)F)C2C(=O)CCCC2=O
StdInChI_Ref
StdInChI1S/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
StdInChIKey_Ref
StdInChIKeyOUBCNLGXQFSTLU-UHFFFAOYSA-N
::

| image = Nitisinone.svg | image_class = skin-invert-image | alt = | image2 = Nitisinone (ball-and-stick).png | image_class2 = bg-transparent | alt2 =

| pronounce = | tradename = Orfadin, others | Drugs.com = | MedlinePlus = | DailyMedID = Nitisinone | pregnancy_AU = | pregnancy_AU_comment = | pregnancy_category = | routes_of_administration = By mouth | class = | ATC_prefix = A16 | ATC_suffix = AX04

| legal_AU = | legal_AU_comment = | legal_BR = | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = | legal_DE = | legal_DE_comment = | legal_NZ = | legal_NZ_comment = | legal_UK = | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = | legal_EU = Rx-only | legal_EU_comment = | legal_UN = | legal_UN_comment = | legal_status =

| bioavailability = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = Approximately 54 h (Range: 39 to 86 hours) | duration_of_action = | excretion =

| CAS_number_Ref = | CAS_number = 104206-65-7 | PubChem = 115355 | IUPHAR_ligand = 6834 | DrugBank_Ref = | DrugBank = DB00348 | ChemSpiderID_Ref = | ChemSpiderID = 103195 | UNII_Ref = | UNII = K5BN214699 | KEGG_Ref = | KEGG = D05177 | ChEBI_Ref = | ChEBI = 50378 | ChEMBL_Ref = | ChEMBL = 1337 | NIAID_ChemDB = | PDB_ligand = | synonyms = NTBC

| IUPAC_name = 2-[2-nitro-4-(trifluoromethyl)benzoyl] cyclohexane-1,3-dione | C = 14 | H = 10 | F = 3 | N = 1 | O = 5 | SMILES = O=C(c1ccc(cc1N+=O)C(F)(F)F)C2C(=O)CCCC2=O | StdInChI_Ref = | StdInChI = 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 | StdInChIKey_Ref = | StdInChIKey = OUBCNLGXQFSTLU-UHFFFAOYSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation =

Nitisinone, sold under the brand name Orfadin among others, is a medication used for the treatment of hereditary tyrosinemia type 1; or for the reduction of urine homogentisic acid in adults with alkaptonuria. Nitisinone is a hydroxyphenyl-pyruvate dioxygenase inhibitor.

It is available as a generic medication.

Medical uses

Nitisinone (Nityr, Orfadin) is indicated for the treatment of hereditary tyrosinemia type 1 in combination with dietary restriction of tyrosine and phenylalanine. Nitisinone (Harliku) is also indicated for the reduction of urine homogentisic acid in adults with alkaptonuria.

Nitisinone is used to treat hereditary tyrosinemia type 1 (HT-1) and alkaptonuria (AKU) in patients from all ages, in combination with dietary restriction of tyrosine and phenylalanine.

Since its first use for this indication in 1991, it has replaced liver transplantation as the first-line treatment for this condition.

It has been shown that nitisinone is toxic to kissing bugs, tsetse, ticks and mosquitoes. The substance may be in the host's bloodstream, or spread on surfaces, as it is absorbed through the mosquito's skin.

Adverse effects

The most common adverse reactions (1%) for nitisinone are elevated tyrosine levels, thrombocytopenia, leukopenia, conjunctivitis, corneal opacity, keratitis, photophobia, eye pain, blepharitis, cataracts, granulocytopenia, epistaxis, pruritus, exfoliative dermatitis, dry skin, maculopapular rash and alopecia. Nitisinone has several negative side effects; these include but are not limited to: bloated abdomen, dark urine, abdominal pain, feeling of tiredness or weakness, headache, light-colored stools, loss of appetite, weight loss, vomiting, and yellow-colored eyes or skin.

Mechanism of action

The mechanism of action of nitisinone involves inhibition of 4-Hydroxyphenylpyruvate dioxygenase (HPPD). This is a treatment for patients with Tyrosinemia type 1 as it prevents the formation of 4-Maleylacetoacetic acid and fumarylacetoacetic acid, which have the potential to be converted to succinyl acetone, a toxin that damages the liver and kidneys.

Alkaptonuria is caused when an enzyme called homogentisic dioxygenase (HGD) is faulty, leading to a buildup of homogentisate (HGA). Alkaptonuria patients treated with nitisinone produce far less HGA than those not treated (95% less in the urine), because nitisinone inhibits HPPD, resulting in less homogenisate accumulation. Clinical trials are ongoing to test whether nitisinone can prevent ochronosis experienced by older alkaptonuria patients

History

Nitisinone was discovered as part of a program to develop a class of herbicides called HPPD inhibitors,[28][29] and it was first synthesized by David L. Lee, a chemist and group leader for this effort at Stauffer Chemical Company. It is a member of the benzoylcyclohexane-1,3-dione family of herbicides, which are chemically derived from a natural phytotoxin, leptospermone, obtained from the Australian bottlebrush plant (Callistemon citrinus). HPPD is essential in plants and animals for catabolism, or breaking apart, of tyrosine. In plants, preventing this process leads to destruction of chlorophyll and the death of the plant. In toxicology studies of the herbicide, it was discovered that it had activity against HPPD in rats and humans.

In type I tyrosinemia, a different enzyme involved in the breakdown of tyrosine, fumarylacetoacetate hydrolase is either absent or mutated and doesn't work, leading to very harmful products building up in the body. Fumarylacetoacetate hydrolase acts on tyrosine after HPPD does, so scientists working on making herbicides in the class of HPPD inhibitors, hypothesized that inhibiting HPPD and controlling tyrosine in the diet could treat this disease. A series of small clinical trials attempted with one of their compounds, nitisinone, were conducted and were successful, leading to nitisinone being brought to market as an orphan drug by Swedish Orphan International, which was later acquired in 2016 by Swedish Orphan Biovitrum (Sobi).

References

References

  1. (14 March 2017). "Health Canada New Drug Authorizations: 2016 Highlights".
  2. (30 November 2021). "Orfadin- nitisinone capsule".
  3. (20 June 2022). "Orfadin- nitisinone suspension".
  4. (24 May 2024). "Nityr- nitisinone tablet".
  5. "Highlights of prescribing information - HARLIKU (nitisinone) tablets, for oral use".
  6. (29 June 2023). "2023 First Generic Drug Approvals".
  7. (30 June 2025). "Harliku (nitisinone) FDA Approval History".
  8. (19 June 2025). "FDA Approves Harliku (nitisinone) for the Treatment of Patients with Alkaptonuria".
  9. (2017). "Clinical utility of nitisinone for the treatment of hereditary tyrosinemia type-1 (HT-1)". The Application of Clinical Genetics.
  10. (1 September 2020). "Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial". The Lancet. Diabetes & Endocrinology.
  11. (2017). "Hereditary Tyrosinemia: Pathogenesis, Screening and Management". Springer International Publishing.
  12. (2006). "Nitisinone in the treatment of hereditary tyrosinaemia type 1". Drugs.
  13. (22 August 2016). "Tyrosine Detoxification Is an Essential Trait in the Life History of Blood-Feeding Arthropods". Current Biology.
  14. (26 January 2021). "Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis". PLOS Biology.
  15. (1 January 2024). "Metabolomic changes associated with acquired resistance to Ixodes scapularis". Ticks and Tick-borne Diseases.
  16. (1 August 2023). "Defining the toxicological profile of 4-hydroxyphenylpyruvate dioxygenase-directed herbicides to Aedes aegypti and Amblyomma americanum". Pesticide Biochemistry and Physiology.
  17. (March 2025). "''Anopheles'' mosquito survival and pharmacokinetic modeling show the mosquitocidal activity of nitisinone". Science Translational Medicine.
  18. (2022). "On the use of inhibitors of 4-hydroxyphenylpyruvate dioxygenase as a vector-selective insecticide in the control of mosquitoes". Pest Management Science.
  19. (July 2025). "The β-triketone, nitisinone, kills insecticide-resistant mosquitoes through cuticular uptake". Parasites & Vectors.
  20. (December 2019). "Long-Term Outcomes and Practical Considerations in the Pharmacological Management of Tyrosinemia Type 1". Paediatric Drugs.
  21. (August 1998). "From toxicological problem to therapeutic use: the discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug". Journal of Inherited Metabolic Disease.
  22. (September 2003). "Interaction of (4-hydroxyphenyl)pyruvate dioxygenase with the specific inhibitor 2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione". Biochemistry.
  23. (26 October 2023). "Alkaptonuria and ochronosis".
  24. (February 2001). "Mesotrione: a new selective herbicide for use in maize". Pest Management Science.
  25. (January 2005). "4-Hydroxyphenylpyruvate dioxygenase". Archives of Biochemistry and Biophysics.
  26. (July 1995). "Inhibition of 4-hydroxyphenylpyruvate dioxygenase by 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione and 2-(2-chloro-4-methanesulfonylbenzoyl)-cyclohexane-1,3-dione". Toxicology and Applied Pharmacology.
  27. (1987). "Metabolism of Aromatic Amino Acids and Amines".
  28. "Physician's Guide to Tyrosinemia Type 1". National Organization for Rare Disorders.
  29. (2016-01-19). "Sobi's Orfadin® oral suspension granted European patent {{!}} Sobi".

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1-nitro-3-(trifluoromethyl)benzene-derivativesherbicidesorphan-drugsaromatic-ketones