Nitisinone is a hydroxyphenylpyruvate dioxygenase inhibitor used as an adjunct to dietary restrictions for the treatment of hereditary tyrosinemia type 1 (HT-1), which causes intolerance to tyrosine containing foods.
- Brand Names
- Nityr, Orfadin
- Generic Name
- DrugBank Accession Number
Nitisinone is a synthetic reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase. It is used in the treatment of hereditary tyrosinemia type 1. It is sold under the brand name Orfadin.
- Small Molecule
- Approved, Investigational
- Average: 329.2281
- Chemical Formula
- External IDs
Used as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1.Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.
- Associated Conditions
- Contraindications & Blackbox Warnings
- Avoid life-threatening adverse drug eventsImprove clinical decision support with information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events & improve clinical decision support.
Hereditary tyrosinemia type 1 occurs due to a deficiency in fumarylacetoacetase (FAH), the final enzyme in the tyrosine catabolic pathway. Nitisinone inhibits catabolism of tyrosine by preventing the catabolic intermediates. 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.
- Mechanism of action
Nitisinone is a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase, an enzyme upstream of fumarylacetoacetate hydrolyase (FAH) in the tyrosine catabolic pathway. By inhibiting the normal catabolism of tyrosine in patients with hereditary tyrosinemia type 1 (HT-1), nitisinone prevents the accumulation of the catabolic intermediates maleylacetoacetate and fumarylacetoacetate.
Target Actions Organism A4-hydroxyphenylpyruvate dioxygenaseinhibitor Humans
The capsule and liquid formulations are bioequivalent in both the plasma concentration-time curve and maximum plasma concentration (Cmax).
- Volume of distribution
- Protein binding
- Not Available
- Route of elimination
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.Improve decision support & research outcomes with our structured adverse effects data.
Side effects include elevated plasma levels of this amino acid, hepatic and liver failure.
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.No interactions found.
- Food Interactions
- Limit the intake of phenylalanine and tyrosine.
- Take separate from meals. Nitisinone capsules should be separated by one hour before or two hours after meals.
- Take with or without food. Nitisinone tablets can be taken with or without food but food may prolong the Tmax by six hours.
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Nitisinone Mdk Capsule 5 mg Oral Mendeli Kabs Europe Ltd 2020-12-16 Not applicable Nitisinone Mdk Capsule 20 mg Oral Mendeli Kabs Europe Ltd 2022-06-08 Not applicable Nitisinone Mdk Capsule 2 mg Oral Mendeli Kabs Europe Ltd 2020-12-16 Not applicable Nitisinone Mdk Capsule 10 mg Oral Mendeli Kabs Europe Ltd 2020-12-16 Not applicable Nitisinone Tablets Tablet 2 mg Oral Cycle Pharmaceuticals Ltd 2017-01-13 Not applicable Nitisinone Tablets Tablet 10 mg Oral Cycle Pharmaceuticals Ltd 2016-12-19 Not applicable Nitisinone Tablets Tablet 5 mg Oral Cycle Pharmaceuticals Ltd 2017-01-13 Not applicable Nityr Tablet 10 mg Oral Cycle Pharmaceuticals (Europe) Ltd 2020-12-22 Not applicable Nityr Tablet 5 mg/1 Oral Cycle Pharmaceuticals Ltd. 2017-07-26 Not applicable Nityr Tablet 2 mg/1 Oral Cycle Pharmaceuticals Ltd. 2017-07-26 Not applicable
- Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Mdk-nitisinone Capsule 2 mg Oral Mendelikabs Inc 2016-10-20 Not applicable Mdk-nitisinone Capsule 10 mg Oral Mendelikabs Inc 2016-10-20 Not applicable Mdk-nitisinone Capsule 20 mg Oral Mendelikabs Inc 2019-02-01 Not applicable Mdk-nitisinone Capsule 5 mg Oral Mendelikabs Inc 2016-10-20 Not applicable Nitisinone Capsule 5 mg/1 Oral Torrent Pharmaceuticals Limited 2023-01-09 Not applicable Nitisinone Capsule 10 mg/1 Oral Par Pharmaceutical, Inc. 2019-10-04 Not applicable Nitisinone Capsule 2 mg/1 Oral Par Pharmaceutical, Inc. 2019-10-04 Not applicable Nitisinone Capsule 2 mg/1 Oral Analog Pharma 2022-06-15 Not applicable Nitisinone Capsule 20 mg/1 Oral Torrent Pharmaceuticals Limited 2023-01-09 Not applicable Nitisinone Capsule 2 mg/1 Oral Novitium Pharma Llc 2019-08-26 Not applicable
- ATC Codes
- A16AX04 — Nitisinone
- Drug Categories
- 4-Hydroxyphenyl-Pyruvate Dioxygenase Inhibitor
- 4-Hydroxyphenylpyruvate Dioxygenase, antagonists & inhibitors
- Acids, Carbocyclic
- Alimentary Tract and Metabolism
- Benzene Derivatives
- Cytochrome P-450 CYP2C9 Inhibitors
- Cytochrome P-450 Enzyme Inhibitors
- Enzyme Inhibitors
- Hydroxyphenylpyruvate Dioxygenase Inhibitors
- Other Miscellaneous Therapeutic Agents
- Various Alimentary Tract and Metabolism Products
- Chemical TaxonomyProvided by Classyfire
- This compound belongs to the class of organic compounds known as benzoylcyclohexane-1,3-diones. These are alkyl-phenylketones where the alkyl group is a cyclohexane 1,3-dione.
- Organic compounds
- Super Class
- Organic oxygen compounds
- Organooxygen compounds
- Sub Class
- Carbonyl compounds
- Direct Parent
- Alternative Parents
- Trifluoromethylbenzenes / Nitrobenzenes / Nitroaromatic compounds / Benzoyl derivatives / Aryl alkyl ketones / Beta-diketones / Cyclic ketones / Propargyl-type 1,3-dipolar organic compounds / Organic oxoazanium compounds / Organopnictogen compounds / Organonitrogen compounds / Organofluorides / Organic oxides / Hydrocarbon derivatives / Alkyl fluorides show 5 more
- 1,3-dicarbonyl compound / 1,3-diketone / Alkyl fluoride / Alkyl halide / Allyl-type 1,3-dipolar organic compound / Aromatic homomonocyclic compound / Aryl alkyl ketone / Benzenoid / Benzoyl / Benzoylcyclohexane-1,3-dione / C-nitro compound / Cyclic ketone / Hydrocarbon derivative / Monocyclic benzene moiety / Nitroaromatic compound / Nitrobenzene / Organic 1,3-dipolar compound / Organic nitro compound / Organic nitrogen compound / Organic oxide / Organic oxoazanium / Organofluoride / Organohalogen compound / Organonitrogen compound / Organopnictogen compound / Propargyl-type 1,3-dipolar organic compound / Trifluoromethylbenzene show 17 more
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- C-nitro compound, (trifluoromethyl)benzenes, cyclohexanones (CHEBI:50378)
- Affected organisms
- Humans and other mammals
- CAS number
- InChI Key
- IUPAC Name
- General References
- Not Available
- FDA label
- Download (194 KB)
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment Hereditary Tyrosinemia, Type I 1 3 Unknown Status Treatment Alkaptonuria 1 2 Completed Treatment Alkaptonuria 2 2, 3 Completed Treatment Alkaptonuria 1 1 Completed Basic Science Drug Drug Interaction (DDI) 1 1 Completed Basic Science Hereditary Tyrosinemia, Type I 3 1 Completed Treatment Healthy Subjects (HS) 2 1 Completed Treatment Hereditary Tyrosinemia, Type I 1 1, 2 Completed Treatment Albinism / Vision Loss 1 Not Available Completed Not Available Hereditary Tyrosinemia, Type I 1
- Rare disease therapeutics inc
- Apoteket Produktion and Laboratorier Ab
- Rare Disease Therapeutics Inc.
- Swedish Orphan International Ab
- Dosage Forms
Form Route Strength Capsule Oral 10 mg Capsule Oral 2 mg Capsule Oral 5 mg Capsule, coated Oral 10 mg Tablet Oral 10 mg Tablet Oral 2 mg Tablet Oral 5 mg Capsule, coated Oral 2 mg Capsule, coated Oral 5 mg Tablet Oral 10 mg/1 Tablet Oral 2 mg/1 Tablet Oral 5 mg/1 Capsule Oral 10 mg/1 Capsule Oral 2 mg/1 Capsule Oral 20 mg Capsule Oral 20 mg/1 Capsule Oral 5 mg/1 Suspension Oral 4 MG/ML Suspension Oral 4 mg/1mL Suspension Oral 4 mg / mL Capsule Oral
Unit description Cost Unit Orfadin 10 mg capsule 308.68USD capsule Orfadin 5 mg capsule 154.34USD capsule Orfadin 2 mg capsule 61.74USD capsuleDrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patent Number Pediatric Extension Approved Expires (estimated) Region US5550165 No 1996-08-27 2013-08-27 US9301932 No 2016-04-05 2033-02-02 US10328029 No 2019-06-25 2035-01-05
- Experimental Properties
Property Value Source logP 1.6 Not Available
- Predicted Properties
Property Value Source Water Solubility 0.00811 mg/mL ALOGPS logP 2.06 ALOGPS logP 3.13 Chemaxon logS -4.6 ALOGPS pKa (Strongest Acidic) 7.44 Chemaxon pKa (Strongest Basic) -7.3 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 94.35 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 71.34 m3·mol-1 Chemaxon Polarizability 26.76 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon
- Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9849 Blood Brain Barrier + 0.87 Caco-2 permeable - 0.5086 P-glycoprotein substrate Non-substrate 0.8491 P-glycoprotein inhibitor I Inhibitor 0.7006 P-glycoprotein inhibitor II Non-inhibitor 0.8517 Renal organic cation transporter Non-inhibitor 0.8355 CYP450 2C9 substrate Non-substrate 0.7862 CYP450 2D6 substrate Non-substrate 0.8292 CYP450 3A4 substrate Substrate 0.5765 CYP450 1A2 substrate Inhibitor 0.5808 CYP450 2C9 inhibitor Non-inhibitor 0.5566 CYP450 2D6 inhibitor Non-inhibitor 0.8867 CYP450 2C19 inhibitor Inhibitor 0.5431 CYP450 3A4 inhibitor Inhibitor 0.6104 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5347 Ames test Non AMES toxic 0.5612 Carcinogenicity Non-carcinogens 0.6585 Biodegradation Not ready biodegradable 0.9836 Rat acute toxicity 2.6075 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.6292 hERG inhibition (predictor II) Non-inhibitor 0.7814
- Mass Spec (NIST)
- Not Available
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
- Pharmacological action
- General Function
- Metal ion binding
- Specific Function
- Key enzyme in the degradation of tyrosine.
- Gene Name
- Uniprot ID
- Uniprot Name
- 4-hydroxyphenylpyruvate dioxygenase
- Molecular Weight
- 44934.12 Da
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
- Fisher AA, Davis MW: Alkaptonuric ochronosis with aortic valve and joint replacements and femoral fracture: a case report and literature review. Clin Med Res. 2004 Nov;2(4):209-15. [Article]
- Yang DY: 4-Hydroxyphenylpyruvate dioxygenase as a drug discovery target. Drug News Perspect. 2003 Oct;16(8):493-6. [Article]
- Hanauske-Abel HM, Popowicz A, Remotti H, Newfield RS, Levy J: Tyrosinemia I, a model for human diseases mediated by 2-oxoacid-utilizing dioxygenases: hepatotoxin suppression by NTBC does not normalize hepatic collagen metabolism. J Pediatr Gastroenterol Nutr. 2002 Jul;35(1):73-8. [Article]
- Suwannarat P, O'Brien K, Perry MB, Sebring N, Bernardini I, Kaiser-Kupfer MI, Rubin BI, Tsilou E, Gerber LH, Gahl WA: Use of nitisinone in patients with alkaptonuria. Metabolism. 2005 Jun;54(6):719-28. [Article]
- Santra S, Baumann U: Experience of nitisinone for the pharmacological treatment of hereditary tyrosinaemia type 1. Expert Opin Pharmacother. 2008 May;9(7):1229-36. doi: 10.1517/146565188.8.131.529. [Article]
Drug created at June 13, 2005 13:24 / Updated at February 08, 2023 20:46