Nitisinone

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Nitisinone
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Clinical data
Trade namesOrfadin, others
Other namesNTBC
AHFS/Drugs.comMonograph
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Routes of
administration		By mouth
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Legal status
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Pharmacokinetic data
Elimination half-lifeApproximately 54 h (Range: 39 to 86 hours)
Identifiers
  • 2-[2-nitro-4-(trifluoromethyl)benzoyl]
    cyclohexane-1,3-dione
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Chemical and physical data
FormulaC14H10F3NO5
Molar mass329.231 g·mol−1
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  • O=C(c1ccc(cc1[N+]([O-])=O)C(F)(F)F)C2C(=O)CCCC2=O
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  • Key:OUBCNLGXQFSTLU-UHFFFAOYSA-N checkY
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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;[2][4] or for the reduction of urine homogentisic acid in adults with alkaptonuria.[5] Nitisinone is a hydroxyphenyl-pyruvate dioxygenase inhibitor.[2][4]

It is available as a generic medication.[6]

Medical uses

Nitisinone (Nityr, Orfadin) is indicated for the treatment of hereditary tyrosinemia type 1 in combination with dietary restriction of tyrosine and phenylalanine.[2][4] Nitisinone (Harliku) is also indicated for the reduction of urine homogentisic acid in adults with alkaptonuria.[5][7][8]

Nitisinone is used to treat hereditary tyrosinemia type 1[9] (HT-1) and alkaptonuria[10] (AKU) in patients from all ages, in combination with dietary restriction of tyrosine and phenylalanine.

Since its first use for this indication in 1991,[11] it has replaced liver transplantation as the first-line treatment for this condition.[12]

It has been shown that nitisinone is toxic to kissing bugs,[13] tsetse,[14] ticks[15][16] and mosquitoes.[17][18] The substance may be in the host's bloodstream, or spread on surfaces, as it is absorbed through the mosquito's skin.[19]

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.[20]

Mechanism of action

The mechanism of action of nitisinone involves inhibition of 4-Hydroxyphenylpyruvate dioxygenase (HPPD).[21][22] 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.[12]

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[23]

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).[24] HPPD is essential in plants and animals for catabolism, or breaking apart, of tyrosine.[25] In plants, preventing this process leads to destruction of chlorophyll and the death of the plant.[25] In toxicology studies of the herbicide, it was discovered that it had activity against HPPD in rats[26] and humans.[27]

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.[28] Fumarylacetoacetate hydrolase acts on tyrosine after HPPD does, so scientists[11] 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,[21] which was later acquired in 2016 by Swedish Orphan Biovitrum (Sobi).[29]

References

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  1. ^ Page Module:Citation/CS1/styles.css has no content."Health Canada New Drug Authorizations: 2016 Highlights". Health Canada. 14 March 2017. Retrieved 7 April 2024.
  2. ^ a b c d Page Module:Citation/CS1/styles.css has no content."Orfadin- nitisinone capsule". DailyMed. 30 November 2021. Retrieved 5 July 2025.
  3. ^ Page Module:Citation/CS1/styles.css has no content."Orfadin- nitisinone suspension". DailyMed. 20 June 2022. Retrieved 5 July 2025.
  4. ^ a b c d Page Module:Citation/CS1/styles.css has no content."Nityr- nitisinone tablet". DailyMed. 24 May 2024. Retrieved 5 July 2025.
  5. ^ a b c Page Module:Citation/CS1/styles.css has no content."Highlights of prescribing information - HARLIKU (nitisinone) tablets, for oral use" (PDF). Archived from the original (PDF) on 23 June 2025.
  6. ^ Page Module:Citation/CS1/styles.css has no content."2023 First Generic Drug Approvals". U.S. Food and Drug Administration (FDA). 29 June 2023. Archived from the original on 29 June 2023. Retrieved 29 June 2023.
  7. ^ Page Module:Citation/CS1/styles.css has no content."Harliku (nitisinone) FDA Approval History". Drugs.com. 30 June 2025. Retrieved 5 July 2025.
  8. ^ Page Module:Citation/CS1/styles.css has no content."FDA Approves Harliku (nitisinone) for the Treatment of Patients with Alkaptonuria". Drugs.com (Press release). 19 June 2025. Retrieved 5 July 2025.
  9. ^ Page Module:Citation/CS1/styles.css has no content.Das AM (2017). "Clinical utility of nitisinone for the treatment of hereditary tyrosinemia type-1 (HT-1)". The Application of Clinical Genetics. 10: 43–48. doi:10.2147/TACG.S113310. ISSN 1178-704X. PMC 5533484. PMID 28769581.
  10. ^ Page Module:Citation/CS1/styles.css has no content.Ranganath LR, Psarelli EE, Arnoux JB, Braconi D, Briggs M, Bröijersén A, et al. (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. 8 (9): 762–772. doi:10.1016/S2213-8587(20)30228-X. hdl:11365/1115671. PMID 32822600.
  11. ^ a b Page Module:Citation/CS1/styles.css has no content.Lock EA (2017). "From Weed Killer to Wonder Drug". In Tanguay RM (ed.). Hereditary Tyrosinemia: Pathogenesis, Screening and Management. Advances in Experimental Medicine and Biology. Vol. 959. Cham: Springer International Publishing. pp. 175–185. doi:10.1007/978-3-319-55780-9_16. ISBN 978-3-319-55780-9. PMID 28755195. Retrieved 21 May 2025.
  12. ^ a b Page Module:Citation/CS1/styles.css has no content.McKiernan PJ (2006). "Nitisinone in the treatment of hereditary tyrosinaemia type 1". Drugs. 66 (6): 743–750. doi:10.2165/00003495-200666060-00002. PMID 16706549. S2CID 24239547.
  13. ^ Page Module:Citation/CS1/styles.css has no content.Perdomo HD, Guizzo MG, Barletta AB, Nunes RD, Dias FA, Sorgine MH, et al. (22 August 2016). "Tyrosine Detoxification Is an Essential Trait in the Life History of Blood-Feeding Arthropods". Current Biology. 26 (16): 2188–2193. Bibcode:2016CBio...26.2188S. doi:10.1016/j.cub.2016.06.025. PMID 27476595.
  14. ^ Page Module:Citation/CS1/styles.css has no content.Haines LR, Casas-Sánchez A, Adung'a VO, Vionette-Amaral RJ, Quek S, Rose C, et al. (26 January 2021). "Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis". PLOS Biology. 19 (1) e3000796. doi:10.1371/journal.pbio.3000796. PMC 7837477. PMID 33497373.
  15. ^ Page Module:Citation/CS1/styles.css has no content.Matias J, Tang X, Cibichakravarthy B, DePonte K, Wu MJ, Fikrig E, et al. (1 January 2024). "Metabolomic changes associated with acquired resistance to Ixodes scapularis". Ticks and Tick-borne Diseases. 15 (1) 102279. doi:10.1016/j.ttbdis.2023.102279. PMID 37972499.
  16. ^ Page Module:Citation/CS1/styles.css has no content.Duke SO, Burgess ER, Swale DR, McComic SE (1 August 2023). "Defining the toxicological profile of 4-hydroxyphenylpyruvate dioxygenase-directed herbicides to Aedes aegypti and Amblyomma americanum". Pesticide Biochemistry and Physiology. 194 105532. Bibcode:2023PBioP.19405532M. doi:10.1016/j.pestbp.2023.105532. PMID 37532340.
  17. ^ Page Module:Citation/CS1/styles.css has no content.Haines LR, Trett A, Rose C, García N, Sterkel M, McGuinness D, et al. (March 2025). "Anopheles mosquito survival and pharmacokinetic modeling show the mosquitocidal activity of nitisinone". Science Translational Medicine. 17 (791) eadr4827. doi:10.1126/scitranslmed.adr4827. PMID 40138457.
  18. ^ Page Module:Citation/CS1/styles.css has no content.Sterkel M, Martins AJ, BP Lima J, L Oliveira P, Vergaray Ramirez MA (2022). "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. doi:10.1002/ps.6679. PMID 34647418.
  19. ^ Page Module:Citation/CS1/styles.css has no content.Stavrou-Dowd ZT, Parsons G, Rose C, Brown F, Lees RS, Acosta-Serrano Á, et al. (July 2025). "The β-triketone, nitisinone, kills insecticide-resistant mosquitoes through cuticular uptake". Parasites & Vectors. 18 (1) 316. doi:10.1186/s13071-025-06939-0. PMC 12315382. PMID 40745331.
  20. ^ Page Module:Citation/CS1/styles.css has no content.Rodenburg IL, Harding CO, Hollak CE, Heiner-Fokkema MR, van Spronsen FJ, van Ginkel WG (December 2019). "Long-Term Outcomes and Practical Considerations in the Pharmacological Management of Tyrosinemia Type 1". Paediatric Drugs. 21 (6): 413–426. doi:10.1007/s40272-019-00364-4. ISSN 1179-2019. PMC 6885500. PMID 31667718.
  21. ^ a b Page Module:Citation/CS1/styles.css has no content.Lock EA, Ellis MK, Gaskin P, Robinson M, Auton TR, Provan WM, et al. (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. 21 (5): 498–506. doi:10.1023/A:1005458703363. PMID 9728330. S2CID 6717818.
  22. ^ Page Module:Citation/CS1/styles.css has no content.Kavana M, Moran GR (September 2003). "Interaction of (4-hydroxyphenyl)pyruvate dioxygenase with the specific inhibitor 2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione". Biochemistry. 42 (34): 10238–10245. doi:10.1021/bi034658b. PMID 12939152.
  23. ^ Page Module:Citation/CS1/styles.css has no content."Alkaptonuria and ochronosis". DermNet. 26 October 2023. Retrieved 22 May 2025.
  24. ^ Page Module:Citation/CS1/styles.css has no content.Mitchell G, Bartlett DW, Fraser TE, Hawkes TR, Holt DC, Townson JK, et al. (February 2001). "Mesotrione: a new selective herbicide for use in maize". Pest Management Science. 57 (2): 120–128. doi:10.1002/1526-4998(200102)57:2<120::AID-PS254>3.0.CO;2-E. PMID 11455642.
  25. ^ a b Page Module:Citation/CS1/styles.css has no content.Moran GR (January 2005). "4-Hydroxyphenylpyruvate dioxygenase". Archives of Biochemistry and Biophysics. 433 (1): 117–128. doi:10.1016/j.abb.2004.08.015. PMID 15581571.
  26. ^ Page Module:Citation/CS1/styles.css has no content.Ellis MK, Whitfield AC, Gowans LA, Auton TR, Provan WM, Lock EA, et al. (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. 133 (1): 12–19. Bibcode:1995ToxAP.133...12E. doi:10.1006/taap.1995.1121. PMID 7597701.
  27. ^ Page Module:Citation/CS1/styles.css has no content.Lindstedt S, Odelhög B (1987). "4-Hydroxyphenylpyruvate dioxygenase from human liver". In Kaufman S (ed.). Metabolism of Aromatic Amino Acids and Amines. Methods in Enzymology. Vol. 142. pp. 139–142. doi:10.1016/S0076-6879(87)42021-1. ISBN 978-0-12-182042-8. PMID 3037254.
  28. ^ Page Module:Citation/CS1/styles.css has no content.Tanguay RM. "Physician's Guide to Tyrosinemia Type 1" (PDF). National Organization for Rare Disorders. Archived from the original (PDF) on 11 February 2014.
  29. ^ Page Module:Citation/CS1/styles.css has no content."Sobi's Orfadin® oral suspension granted European patent | Sobi". www.sobi.com. 19 January 2016. Retrieved 6 July 2025.

Further reading

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