From Wikipedia, the free encyclopedia
Jump to: navigation, search
Systematic (IUPAC) name
Clinical data
AHFS/ Consumer Drug Information
Licence data EMA:Link, US FDA:link
Legal status
Routes Oral
Pharmacokinetic data
Half-life Approximately 54 h
CAS number 104206-65-7 YesY
ATC code A16AX04
PubChem CID 115355
DrugBank DB00348
ChemSpider 103195 YesY
UNII K5BN214699 YesY
KEGG D05177 YesY
ChEBI CHEBI:50378 YesY
Chemical data
Formula C14H10F3NO5 
Mol. mass 329.228 g/mol
 YesY (what is this?)  (verify)

Nitisinone (also known as NTBC, an abbreviation of its full chemical name) is a drug used to slow the effects of hereditary tyrosinemia type 1. Since its first use for this indication in 1991, it has replaced liver transplantation as the first-line treatment for this rare condition. It is also being studied in the related condition alkaptonuria. It is marketed under the brand name Orfadin by the company, Swedish Orphan Biovitrum (Sobi) after having originally been brought to market by Swedish Orphan International. It was originally developed as candidate herbicide.


Nitisinone is used to treat hereditary tyrosinemia type 1, in combination with restriction of tyrosine in the diet.[1][2][3]

Since its first use for this indication in 1991, it has replaced liver transplantation as the first-line treatment for this rare condition.[4] I It is marketed under the brand name Orfadin.

It has been demonstrated that treatment with nitisinone can reduce urinary levels of homogentisic acid in alkaptonuria patients by 95%.[5] A series of clinical trials run by DevelopAKUre to determine whether nitisinone is effective at treating the ochronosis suffered by patients with alkaptonuria are ongoing.[6] If the trials are successful, DevelopAKUre will try to get nitisinone licensed for use by alkaptonuria patients.[7]

Mechanism of action[edit]

The mechanism of action of nitisinone involves reversibile inhibition of 4-Hydroxyphenylpyruvate dioxygenase (HPPD),.[8][9] This is a treatment for patients with Tyrosinemia type 1 as it prevents the formation of maleylacetoacetic acid and fumarylacetoacetic acid, which have the potential to be converted to succinyl acetone, a toxin that damages the liver and kidneys.[4] This causes the symptoms of Tyrosinemia type 1 experienced by untreated patients.[10]

Alkaptonuria is caused when an enzyme called homogentisic dioxygenase (HGD) is faulty so can't break down homogentisic acid (HGA).[11]Alkaptonuria patients treated with nitisinone produce far less HGA than those not treated (95% less in the urine),[5] because nitisinone inhibits HPPD meaning HGA doesn't form in the first place. Clinical trials are ongoing to test whether nitisinone could prevent the ochronosis experienced by older alkaptonuria patients.[6]

Adverse effects[edit]

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.[12]


Nitisinone is being studied as a treatment for alkaptonuria.[13]

Research at the National Institutes of Health (NIH) has demonstrated that nitisinone can reduce urinary levels of HGA by up to 95% in patients with alkaptonuria.[14] The primary parameter of the NIH trial was range of hip motion, for which the results were inconclusive.

Research done using alkaptonuric mice has shown that mice treated with nitisinone experience no ochronosis in knee joint cartilage. In contrast, all of the mice in the untreated control group developed ochronotic knee joints.[15]

The efficacy of Nitisinone is now being studied in a series international clinical trials called DevelopAKUre.[16] The studies will recruit alkaptonuria patients in Europe.[17] A larger number of patients will be recruited in these trials than in the previous NIH trial.[14][18] The trials are funded by the European Commission.[19]

Nitisinone has been shown to increase skin and eye pigmentation in mice, and has been suggested as a possible treatment for oculocutaneous albinism.[20][21][22]


Nitisinone was discovered as part of a program to develop a class of herbicides called HPPD inhibitors. 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 mutated and doesn't work, leading to very harmful products building up in the body.[1] 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 Swedish Orphan International,[26] which was later acquired by Swedish Orphan Biovitrum (Sobi).

Sobi is now a part of the DevelopAKUre consortium. They are responsible for drug supply and regulatory support in the ongoing clinical trials that will test the efficiacy of nitisinone as a treatment for alkaptonuria.[27] It is hoped that if the trials are successful, nitisinone could also be licensed for treatment of alkaptonuria.[7]


  1. ^ a b National Organization for Rare Disorders. Physician’s Guide to Tyrosinemia Type 1
  2. ^
  3. ^ Sobi Orfadin® (nitisinone)
  4. ^ a b McKiernan PJ (2006). "Nitisinone in the treatment of hereditary tyrosinaemia type 1". Drugs 66 (6): 743–50. doi:10.2165/00003495-200666060-00002. PMID 16706549. 
  5. ^ a b
  6. ^ a b
  7. ^ a b
  8. ^ Lock EA, Ellis MK, Gaskin P, Robinson M, Auton TR, Provan WM, Smith LL, Prisbylla MP, Mutter LC, Lee DL (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 42 (21): 498–506. doi:10.1023/A:1005458703363. PMID 9728330. 
  9. ^ Kavana M, Moran GR (2003). "Interaction of (4-hydroxyphenyl)pyruvate dioxygenase with the specific inhibitor 2-[2-nitro-4-(trifluoromethyl)benzoyl]-1,3-cyclohexanedione". Biochemistry 42 (34): 10238–45. doi:10.1021/bi034658b. PMID 12939152. 
  10. ^
  11. ^
  12. ^
  13. ^ Phornphutkul C, Introne WJ, Perry MB et al. (2002). "Natural history of alkaptonuria". New England Journal Medicine 347 (26): 2111–21. doi:10.1056/NEJMoa021736. PMID 12501223. 
  14. ^ a b file:///C:/Users/AKUSociety/Downloads/nihms-300591.pdf
  15. ^
  16. ^
  17. ^
  18. ^
  19. ^
  20. ^
  21. ^
  22. ^
  23. ^ a b Moran GR. 4-Hydroxyphenylpyruvate dioxygenase Arch Biochem Biophys. 2005 Jan 1;433(1):117-28. PMID 15581571
  24. ^ Ellis, M.K., A.C. Whitfield, L.A. Gowans, T.R. Auton, W.M. Provan, E.A. Lock and L.L. Smith 1995, Inhibition of 4-hydroxyphenylpyruvate dioxygenase by 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione and 2-(2-chloro-4-methylsulfonylbenzoyl)-cyclohexane-1,3-dione. Toxicol. Appl Pharmacol. 133:12-19
  25. ^ Lindsted, W. and B. Odelhög , 4-Hydroxyphenylpyruvate dioxygenase from human liver (1987) Methods Enzymol. 142;139-142
  26. ^ Lock EA et al. 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. J Inherit Metab Dis. 1998 Aug;21(5):498-506. PMID 9728330
  27. ^

External links[edit]