Chemistry:Nitisinone

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Nitisinone, sold under the brand name Orfadin among others, is a medication used for the treatment of hereditary tyrosinemia type 1;[1][2] or for the reduction of urine homogentisic acid in adults with alkaptonuria.[3] Nitisinone is a hydroxyphenyl-pyruvate dioxygenase inhibitor.[1][2]

It is available as a generic medication.[4]

Medical uses

Nitisinone (Nityr, Orfadin) is indicated for the treatment of hereditary tyrosinemia type 1 in combination with dietary restriction of tyrosine and phenylalanine.[1][2] Nitisinone (Harliku) is also indicated for the reduction of urine homogentisic acid in adults with alkaptonuria.[3][5][6]

Nitisinone is used to treat hereditary tyrosinemia type 1[7] (HT-1) and alkaptonuria[8] (AKU) in patients from all ages, in combination with dietary restriction of tyrosine and phenylalanine.

Since its first use for this indication in 1991,[9] it has replaced liver transplantation as the first-line treatment for this condition.[10]

It has been shown that nitisinone is toxic to kissing bugs,[11] tsetse,[12] ticks[13][14] and mosquitoes.[15][16]. The substance may be in the host's bloodstream, or spread on surfaces, as it is absorbed through the mosquito's skin.[17]

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.[18]

Mechanism of action

The mechanism of action of nitisinone involves inhibition of 4-Hydroxyphenylpyruvate dioxygenase (HPPD).[19][20] 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.[10]

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[21]

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).[22] HPPD is essential in plants and animals for catabolism, or breaking apart, of tyrosine.[23] In plants, preventing this process leads to destruction of chlorophyll and the death of the plant.[23] In toxicology studies of the herbicide, it was discovered that it had activity against HPPD in rats[24] and humans.[25]

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.[26] Fumarylacetoacetate hydrolase acts on tyrosine after HPPD does, so scientists[9] 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,[19] which was later acquired in 2016 by Swedish Orphan Biovitrum (Sobi).[27]

References

  1. ↑ 1.0 1.1 1.2 Cite error: Invalid <ref> tag; no text was provided for refs named Orfadin FDA label
  2. ↑ 2.0 2.1 2.2 Cite error: Invalid <ref> tag; no text was provided for refs named Nityr FDA label
  3. ↑ 3.0 3.1 Cite error: Invalid <ref> tag; no text was provided for refs named Harliku FDA label
  4. ↑ "2023 First Generic Drug Approvals". 29 June 2023. https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/2023-first-generic-drug-approvals. 
  5. ↑ "Harliku (nitisinone) FDA Approval History". 30 June 2025. https://www.drugs.com/history/harliku.html. 
  6. ↑ "FDA Approves Harliku (nitisinone) for the Treatment of Patients with Alkaptonuria". Drugs.com (Press release). 19 June 2025. Retrieved 5 July 2025.
  7. ↑ "Clinical utility of nitisinone for the treatment of hereditary tyrosinemia type-1 (HT-1)". The Application of Clinical Genetics 10: 43–48. 2017. doi:10.2147/TACG.S113310. ISSN 1178-704X. PMID 28769581. 
  8. ↑ "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 8 (9): 762–772. 1 September 2020. doi:10.1016/S2213-8587(20)30228-X. PMID 32822600. 
  9. ↑ 9.0 9.1 "From Weed Killer to Wonder Drug". Hereditary Tyrosinemia: Pathogenesis, Screening and Management. Advances in Experimental Medicine and Biology. 959. Cham: Springer International Publishing. 2017. pp. 175–185. doi:10.1007/978-3-319-55780-9_16. ISBN 978-3-319-55780-9. https://link.springer.com/chapter/10.1007/978-3-319-55780-9_16. Retrieved 21 May 2025. 
  10. ↑ 10.0 10.1 "Nitisinone in the treatment of hereditary tyrosinaemia type 1". Drugs 66 (6): 743–750. 2006. doi:10.2165/00003495-200666060-00002. PMID 16706549. 
  11. ↑ "Tyrosine Detoxification Is an Essential Trait in the Life History of Blood-Feeding Arthropods". Current Biology 26 (16): 2188–2193. 22 August 2016. doi:10.1016/j.cub.2016.06.025. PMID 27476595. Bibcode: 2016CBio...26.2188S. 
  12. ↑ "Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis". PLOS Biology 19 (1). 26 January 2021. doi:10.1371/journal.pbio.3000796. PMID 33497373. 
  13. ↑ "Metabolomic changes associated with acquired resistance to Ixodes scapularis". Ticks and Tick-borne Diseases 15 (1). 1 January 2024. doi:10.1016/j.ttbdis.2023.102279. PMID 37972499. 
  14. ↑ "Defining the toxicological profile of 4-hydroxyphenylpyruvate dioxygenase-directed herbicides to Aedes aegypti and Amblyomma americanum". Pesticide Biochemistry and Physiology 194. 1 August 2023. doi:10.1016/j.pestbp.2023.105532. PMID 37532340. Bibcode: 2023PBioP.19405532M. 
  15. ↑ "Anopheles mosquito survival and pharmacokinetic modeling show the mosquitocidal activity of nitisinone". Science Translational Medicine 17 (791). March 2025. doi:10.1126/scitranslmed.adr4827. PMID 40138457. 
  16. ↑ "On the use of inhibitors of 4-hydroxyphenylpyruvate dioxygenase as a vector-selective insecticide in the control of mosquitoes". Pest Management Science 78 (2): 692–702. 2022. doi:10.1002/ps.6679. PMID 34647418. 
  17. ↑ "The β-triketone, nitisinone, kills insecticide-resistant mosquitoes through cuticular uptake". Parasites & Vectors 18 (1). July 2025. doi:10.1186/s13071-025-06939-0. PMID 40745331. 
  18. ↑ "Long-Term Outcomes and Practical Considerations in the Pharmacological Management of Tyrosinemia Type 1". Paediatric Drugs 21 (6): 413–426. December 2019. doi:10.1007/s40272-019-00364-4. ISSN 1179-2019. PMID 31667718. 
  19. ↑ 19.0 19.1 "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 21 (5): 498–506. August 1998. doi:10.1023/A:1005458703363. PMID 9728330. 
  20. ↑ "Interaction of (4-hydroxyphenyl)pyruvate dioxygenase with the specific inhibitor 2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione". Biochemistry 42 (34): 10238–10245. September 2003. doi:10.1021/bi034658b. PMID 12939152. 
  21. ↑ "Alkaptonuria and ochronosis". 26 October 2023. https://dermnetnz.org/topics/alkaptonuria-and-ochronosis#:~:text=Firstly%20patients%20suffer%20low%20back%20pain%20with,spinal%20injuries%20such%20as%20prolapsed%20intervertebral%20discs.. 
  22. ↑ "Mesotrione: a new selective herbicide for use in maize". Pest Management Science 57 (2): 120–128. February 2001. doi:10.1002/1526-4998(200102)57:2<120::AID-PS254>3.0.CO;2-E. PMID 11455642. 
  23. ↑ 23.0 23.1 "4-Hydroxyphenylpyruvate dioxygenase". Archives of Biochemistry and Biophysics 433 (1): 117–128. January 2005. doi:10.1016/j.abb.2004.08.015. PMID 15581571. 
  24. ↑ "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 133 (1): 12–19. July 1995. doi:10.1006/taap.1995.1121. PMID 7597701. Bibcode: 1995ToxAP.133...12E. 
  25. ↑ "4-Hydroxyphenylpyruvate dioxygenase from human liver". Metabolism of Aromatic Amino Acids and Amines. Methods in Enzymology. 142. 1987. pp. 139–142. doi:10.1016/S0076-6879(87)42021-1. ISBN 978-0-12-182042-8. 
  26. ↑ "Physician's Guide to Tyrosinemia Type 1". National Organization for Rare Disorders. https://www.rarediseases.org/docs/Tyrosinemia2_3_11.pdf. 
  27. ↑ "Sobi's Orfadin® oral suspension granted European patent | Sobi" (in en). 2016-01-19. https://www.sobi.com/en/press-releases/sobis-orfadinr-oral-suspension-granted-european-patent-1452320. 

Further reading



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