Identification

Name
Nitisinone
Accession Number
DB00348  (APRD01141)
Type
Small Molecule
Groups
Approved, Investigational
Description

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.

Structure
Thumb
Synonyms
  • 2-(alpha,alpha,alpha-Trifluoro-2-nitro-p-tuluoyl)-1,3-cyclohexanedione
  • Nitisinona
  • Nitisinonum
External IDs
SC-0735
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Nitisinone TabletsTablet2 mgOralCycle Pharmaceuticals Ltd2017-01-13Not applicableCanada
Nitisinone TabletsTablet10 mgOralCycle Pharmaceuticals Ltd2016-12-19Not applicableCanada
Nitisinone TabletsTablet5 mgOralCycle Pharmaceuticals Ltd2017-01-13Not applicableCanada
NityrTablet2 mg/1OralCycle Pharmaceuticals Ltd.2017-07-26Not applicableUs
NityrTablet10 mg/1OralCycle Pharmaceuticals Ltd.2017-07-26Not applicableUs
NityrTablet5 mg/1OralCycle Pharmaceuticals Ltd.2017-07-26Not applicableUs
OrfadinCapsule5 mgOralSWEDISH ORPHAN BIOVITRUM AB (PUBL)2017-02-17Not applicableCanada
OrfadinCapsule5 mg/1OralSWEDISH ORPHAN BIOVITRUM AB (PUBL)2016-07-01Not applicableUs
OrfadinSuspension4 mg/1mLOralSWEDISH ORPHAN BIOVITRUM AB (PUBL)2016-06-01Not applicableUs
OrfadinCapsule2 mg/1OralRare Disease Therapeutics, Inc.2002-01-182015-07-31Us
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Mdk-nitisinoneCapsule20 mgOralMendelikabs IncNot applicableNot applicableCanada
Mdk-nitisinoneCapsule2 mgOralMendelikabs Inc2016-10-20Not applicableCanada
Mdk-nitisinoneCapsule10 mgOralMendelikabs Inc2016-10-20Not applicableCanada
Mdk-nitisinoneCapsule5 mgOralMendelikabs Inc2016-10-20Not applicableCanada
International/Other Brands
Orfadin
Categories
UNII
K5BN214699
CAS number
104206-65-7
Weight
Average: 329.2281
Monoisotopic: 329.05110705
Chemical Formula
C14H10F3NO5
InChI Key
OUBCNLGXQFSTLU-UHFFFAOYSA-N
InChI
InChI=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
IUPAC Name
2-[2-nitro-4-(trifluoromethyl)benzoyl]cyclohexane-1,3-dione
SMILES
[O-][N+](=O)C1=C(C=CC(=C1)C(F)(F)F)C(=O)C1C(=O)CCCC1=O

Pharmacology

Indication

Used as an adjunct to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1.

Associated Conditions
Pharmacodynamics

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.

TargetActionsOrganism
A4-hydroxyphenylpyruvate dioxygenase
inhibitor
Human
Absorption

The capsule and liquid formulations are bioequivalent in both the plasma concentration-time curve and maximum plasma concentration (Cmax).

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

~54 hours

Clearance
Not Available
Toxicity

Side effects include elevated plasma levels of this amino acid, hepatic and liver failure.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
No interactions found.
Food Interactions
Not Available

References

General References
Not Available
External Links
Human Metabolome Database
HMDB0014492
PubChem Compound
115355
PubChem Substance
46507380
ChemSpider
103195
BindingDB
50088804
ChEBI
50378
ChEMBL
CHEMBL1337
Therapeutic Targets Database
DAP000774
PharmGKB
PA164777037
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Nitisinone
ATC Codes
A16AX04 — Nitisinone
AHFS Codes
  • 92:92.00 — Other Miscellaneous Therapeutic Agents
FDA label
Download (194 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceDrug Drug Interactions1
1CompletedBasic ScienceHereditary Tyrosinemia, Type I3
1CompletedTreatmentHealthy Volunteers2
1CompletedTreatmentHereditary Tyrosinemia, Type I1
1, 2CompletedTreatmentAlbinism / Loss of Vision1
2CompletedTreatmentAlkaptonuria2
2, 3Active Not RecruitingTreatmentAlkaptonuria1
3Active Not RecruitingTreatmentAlkaptonuria1
3CompletedTreatmentHereditary Tyrosinemia, Type I1
Not AvailableCompletedPreventionAcidosis, Respiratory / Disease, Chronic1
Not AvailableRecruitingNot AvailableHereditary Tyrosinemia, Type I1

Pharmacoeconomics

Manufacturers
  • Rare disease therapeutics inc
Packagers
  • Apoteket Produktion and Laboratorier Ab
  • Rare Disease Therapeutics Inc.
  • Swedish Orphan International Ab
Dosage forms
FormRouteStrength
CapsuleOral10 mg
CapsuleOral2 mg
CapsuleOral5 mg
TabletOral10 mg
TabletOral2 mg
TabletOral5 mg
TabletOral10 mg/1
TabletOral2 mg/1
TabletOral5 mg/1
CapsuleOral10 mg/1
CapsuleOral2 mg/1
CapsuleOral20 mg
CapsuleOral20 mg/1
CapsuleOral5 mg/1
SuspensionOral4 mg/1mL
SuspensionOral4 mg
Prices
Unit descriptionCostUnit
Orfadin 10 mg capsule308.68USD capsule
Orfadin 5 mg capsule154.34USD capsule
Orfadin 2 mg capsule61.74USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5550165No1993-08-272013-08-27Us
US9301932No2013-02-022033-02-02Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP1.6Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00811 mg/mLALOGPS
logP2.06ALOGPS
logP3.13ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)2.71ChemAxon
pKa (Strongest Basic)-7.3ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area97.03 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity72.35 m3·mol-1ChemAxon
Polarizability26.74 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9849
Blood Brain Barrier+0.87
Caco-2 permeable-0.5086
P-glycoprotein substrateNon-substrate0.8491
P-glycoprotein inhibitor IInhibitor0.7006
P-glycoprotein inhibitor IINon-inhibitor0.8517
Renal organic cation transporterNon-inhibitor0.8355
CYP450 2C9 substrateNon-substrate0.7862
CYP450 2D6 substrateNon-substrate0.8292
CYP450 3A4 substrateSubstrate0.5765
CYP450 1A2 substrateInhibitor0.5808
CYP450 2C9 inhibitorNon-inhibitor0.5566
CYP450 2D6 inhibitorNon-inhibitor0.8867
CYP450 2C19 inhibitorInhibitor0.5431
CYP450 3A4 inhibitorInhibitor0.6104
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5347
Ames testNon AMES toxic0.5612
CarcinogenicityNon-carcinogens0.6585
BiodegradationNot ready biodegradable0.9836
Rat acute toxicity2.6075 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6292
hERG inhibition (predictor II)Non-inhibitor0.7814
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
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.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Carbonyl compounds
Direct Parent
Benzoylcyclohexane-1,3-diones
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
show 5 more
Substituents
Benzoylcyclohexane-1,3-dione / Trifluoromethylbenzene / Nitrobenzene / Benzoyl / Nitroaromatic compound / Aryl alkyl ketone / 1,3-diketone / Monocyclic benzene moiety / 1,3-dicarbonyl compound / Benzenoid
show 17 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
C-nitro compound, (trifluoromethyl)benzenes, cyclohexanones (CHEBI:50378)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Key enzyme in the degradation of tyrosine.
Gene Name
HPD
Uniprot ID
P32754
Uniprot Name
4-hydroxyphenylpyruvate dioxygenase
Molecular Weight
44934.12 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. 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. [PubMed:15931360]
  3. Yang DY: 4-Hydroxyphenylpyruvate dioxygenase as a drug discovery target. Drug News Perspect. 2003 Oct;16(8):493-6. [PubMed:14668946]
  4. 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. [PubMed:12142814]
  5. 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. [PubMed:15931605]
  6. 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: 10.1517/14656566.9.7.1229. [PubMed:18422479]

Drug created on June 13, 2005 07:24 / Updated on October 16, 2018 08:25