Nitisinone
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MedKoo CAT#: 314265

CAS#: 104206-65-7

Description: Nitisinone, also known as NTBC, is an effective herbicide, is the licensed treatment for the human condition, hereditary tyrosinaemia type 1 (HT-1). Its mode of action interrupts tyrosine metabolism through inhibition of 4-hydroxyphenylpyruvate dioxygenase (HPPD). Nitisinone is a remarkable safe drug to use with few side effects reported.

Chemical Structure

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Nitisinone
CAS# 104206-65-7
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 314265
Name: Nitisinone
CAS#: 104206-65-7
Chemical Formula: C14H10F3NO5
Exact Mass: 329.05
Molecular Weight: 329.230
Elemental Analysis: C, 51.07; H, 3.06; F, 17.31; N, 4.25; O, 24.30

Price and Availability

Size Price Availability Quantity
100mg USD 150 Ready to ship
250mg USD 250 Ready to ship
500mg USD 350 Ready to ship
1g USD 450 Ready to ship
2g USD 650 Ready to ship
5g USD 950 Ready to ship
10g USD 1450 Ready to ship
20g USD 2250 Ready to ship
50g USD 4650 Ready to ship
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Synonym: NTBC; Nitisinone; brand name: Orfadin.

IUPAC/Chemical Name: 2-(2-nitro-4-(trifluoromethyl)benzoyl)cyclohexane-1,3-dione

InChi Key: OUBCNLGXQFSTLU-UHFFFAOYSA-N

InChi Code: 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

SMILES Code: O=C1C(C(C2=CC=C(C(F)(F)F)C=C2[N+]([O-])=O)=O)C(CCC1)=O

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO.

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:

Biological target: Nitisinone(SC0735) is an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase.
In vitro activity: Nitisinone's effect on chondrocytes and osteoblast-like cells was analyzed in an in vitro model. Human C20/A4 immortalized chondrocytes, and osteosarcoma cells MG63 cultured in DMEM, as previously described. Confluent cells were then plated into 24-well plates at 4 × 10(4) cells per well in varying concentrations of nitisinone. Cells were cultured for 7 days with medium changes every third day. Trypan blue assay was used to determine viability and the effect of nitisinone concentration on cells. Statistical analysis was performed using analysis of variance, and differences between groups were determined by Newman-Keuls post-test. Analysis of C20/A4 chondrocyte and MG63 osteoblast-like cell viability when cultured in different concentrations of nitisinone demonstrates that there is no statistically significant difference in cell viability compared to control cultures. There is currently no literature surrounding the use of nitisinone in human in vitro models, or its effect on chondrocytes or osteoblast like cells. These results show that nitisinone does not appear detrimental to cell viability of chondrocytes or osteoblast-like cells, which adds to the evidence that this therapy could be useful in treating AKU. Reference: Clin Rheumatol. 2016 Feb;35(2):513-6. https://dx.doi.org/10.1007/s10067-015-2983-1
In vivo activity: Treatment with nitisinone increased tyrosine levels nearly 7-fold, resulting in an average concentration of 553 μM in the treated group compared with 80 μM in the control group, and much higher than the baseline tyrosine plasma content in other Tyr mutant mouse strains such as Tyrc-h/c-h (74–99 μM) and Tyrc-2J/c-2J (109–139 μM). Even though plasma tyrosine was substantially elevated, no discernible side effects were observed. The treated mice did not exhibit abnormal behavior or develop gross skin or corneal lesions, which can be side effects of hypertyrosinemia in humans. To quantify the effect of nitisinone on the number and size of melanosomes in ocular tissue, TEM of the iris, choroid, and RPE was performed (one eye each from n = 7 treated and n = 7 control mice) (Fig. 3). On processing of the images using ImageJ, and analysis of the data using two-tailed t-test, no statistically significant difference between the number of melanosomes in the RPE and choroid of treated compared with control mice was found (Fig. 4). However, it was detected that a statistically significant difference in the number of pigmented melanosomes in the iris stroma of the treated mice compared with untreated (Fig. 4). The cross-sectional area of melanosomes did not differ significantly between the two groups (Fig. 5). Melanosomes from all ocular tissues were between 0.048 and 0.8 μm2 in size and comparable to previously published melanosome size in choroid (0.07 ± 0.04 μm2) and RPE (0.12 ± 0.08 μm2) of wild-type C57BL/6J mice.40 These data demonstrate that treatment with nitisinone does not have a major impact on melanin pigmentation at either the gross or microscopic level in the C57BL/6J-Tyrp1b-J/b-J mouse model of OCA3. Reference: Invest Ophthalmol Vis Sci. 2018 Oct 1;59(12):4945-4952. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30347088/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 30.0 91.10

Preparing Stock Solutions

The following data is based on the product molecular weight 329.23 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
In vitro protocol: 1. Mistry JB, Jackson DJ, Bukhari M, Taylor AM. Osteoarticular cells tolerate short-term exposure to nitisinone-implications in alkaptonuria. Clin Rheumatol. 2016 Feb;35(2):513-6. doi: 10.1007/s10067-015-2983-1. Epub 2015 May 31. PMID: 26024586.
In vivo protocol: 1. Onojafe IF, Megan LH, Melch MG, Aderemi JO, Alur RP, Abu-Asab MS, Chan CC, Bernardini IM, Albert JS, Cogliati T, Adams DR, Brooks BP. Minimal Efficacy of Nitisinone Treatment in a Novel Mouse Model of Oculocutaneous Albinism, Type 3. Invest Ophthalmol Vis Sci. 2018 Oct 1;59(12):4945-4952. doi: 10.1167/iovs.16-20293. PMID: 30347088; PMCID: PMC6181301. 2. Onojafe IF, Adams DR, Simeonov DR, Zhang J, Chan CC, Bernardini IM, Sergeev YV, Dolinska MB, Alur RP, Brilliant MH, Gahl WA, Brooks BP. Nitisinone improves eye and skin pigmentation defects in a mouse model of oculocutaneous albinism. J Clin Invest. 2011 Oct;121(10):3914-23. doi: 10.1172/JCI59372. PMID: 21968110; PMCID: PMC3223618.

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1: Souri E, Lahiji FR, Nourhashemi T, Jalalizadeh H. A Stability Indicating HPLC Method for the Determination of Nitisinone in Capsules. Indian J Pharm Sci. 2015 May-Jun;77(3):348-51. PubMed PMID: 26180282; PubMed Central PMCID: PMC4502151.

2: Simoncelli M, Samson J, Bussières JF, Lacroix J, Dorais M, Battista R, Perreault S. Cost-Consequence Analysis of Nitisinone for Treatment of Tyrosinemia Type I. Can J Hosp Pharm. 2015 May-Jun;68(3):210-7. PubMed PMID: 26157182; PubMed Central PMCID: PMC4485508.

3: Mistry JB, Jackson DJ, Bukhari M, Taylor AM. Osteoarticular cells tolerate short-term exposure to nitisinone-implications in alkaptonuria. Clin Rheumatol. 2015 May 31. [Epub ahead of print] PubMed PMID: 26024586.

4: Keenan CM, Preston AJ, Sutherland H, Wilson PJ, Psarelli EE, Cox TF, Ranganath LR, Jarvis JC, Gallagher JA. Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice. JIMD Rep. 2015;24:45-50. doi: 10.1007/8904_2015_437. Epub 2015 May 5. PubMed PMID: 25940034; PubMed Central PMCID: PMC4582025.

5: Olsson B, Cox TF, Psarelli EE, Szamosi J, Hughes AT, Milan AM, Hall AK, Rovensky J, Ranganath LR. Relationship Between Serum Concentrations of Nitisinone and Its Effect on Homogentisic Acid and Tyrosine in Patients with Alkaptonuria. JIMD Rep. 2015;24:21-7. doi: 10.1007/8904_2015_412. Epub 2015 Mar 13. PubMed PMID: 25772318; PubMed Central PMCID: PMC4582028.

6: Gertsman I, Barshop BA, Panyard-Davis J, Gangoiti JA, Nyhan WL. Metabolic Effects of Increasing Doses of Nitisinone in the Treatment of Alkaptonuria. JIMD Rep. 2015;24:13-20. doi: 10.1007/8904_2014_403. Epub 2015 Feb 10. PubMed PMID: 25665838; PubMed Central PMCID: PMC4582031.

7: Hughes AT, Milan AM, Davison AS, Christensen P, Ross G, Gallagher JA, Dutton JJ, Ranganath LR. Serum markers in alkaptonuria: simultaneous analysis of homogentisic acid, tyrosine and nitisinone by liquid chromatography tandem mass spectrometry. Ann Clin Biochem. 2015 Sep;52(Pt 5):597-605. doi: 10.1177/0004563215571969. Epub 2015 Jan 27. PubMed PMID: 25628464.

8: Ranganath LR, Milan AM, Hughes AT, Dutton JJ, Fitzgerald R, Briggs MC, Bygott H, Psarelli EE, Cox TF, Gallagher JA, Jarvis JC, van Kan C, Hall AK, Laan D, Olsson B, Szamosi J, Rudebeck M, Kullenberg T, Cronlund A, Svensson L, Junestrand C, Ayoob H, Timmis OG, Sireau N, Le Quan Sang KH, Genovese F, Braconi D, Santucci A, Nemethova M, Zatkova A, McCaffrey J, Christensen P, Ross G, Imrich R, Rovensky J. Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment. Ann Rheum Dis. 2014 Dec 4. pii: annrheumdis-2014-206033. doi: 10.1136/annrheumdis-2014-206033. [Epub ahead of print] PubMed PMID: 25475116.

9: Lock E, Ranganath LR, Timmis O. The role of nitisinone in tyrosine pathway disorders. Curr Rheumatol Rep. 2014 Nov;16(11):457. doi: 10.1007/s11926-014-0457-0. Review. PubMed PMID: 25266991.

10: Stewart RM, Briggs MC, Jarvis JC, Gallagher JA, Ranganath L. Reversible keratopathy due to hypertyrosinaemia following intermittent low-dose nitisinone in alkaptonuria: a case report. JIMD Rep. 2014;17:1-6. doi: 10.1007/8904_2014_307. Epub 2014 Jul 6. PubMed PMID: 24997710; PubMed Central PMCID: PMC4241204.

11: Bartlett DC, Lloyd C, McKiernan PJ, Newsome PN. Early nitisinone treatment reduces the need for liver transplantation in children with tyrosinaemia type 1 and improves post-transplant renal function. J Inherit Metab Dis. 2014 Sep;37(5):745-52. doi: 10.1007/s10545-014-9683-x. Epub 2014 Feb 11. PubMed PMID: 24515874.

12: Bendadi F, de Koning TJ, Visser G, Prinsen HC, de Sain MG, Verhoeven-Duif N, Sinnema G, van Spronsen FJ, van Hasselt PM. Impaired cognitive functioning in patients with tyrosinemia type I receiving nitisinone. J Pediatr. 2014 Feb;164(2):398-401. doi: 10.1016/j.jpeds.2013.10.001. Epub 2013 Nov 14. PubMed PMID: 24238861.

13: Preston AJ, Keenan CM, Sutherland H, Wilson PJ, Wlodarski B, Taylor AM, Williams DP, Ranganath LR, Gallagher JA, Jarvis JC. Ochronotic osteoarthropathy in a mouse model of alkaptonuria, and its inhibition by nitisinone. Ann Rheum Dis. 2014 Jan;73(1):284-9. doi: 10.1136/annrheumdis-2012-202878. Epub 2013 Mar 19. PubMed PMID: 23511227.

14: Vanclooster A, Devlieger R, Meersseman W, Spraul A, Kerckhove KV, Vermeersch P, Meulemans A, Allegaert K, Cassiman D. Pregnancy during nitisinone treatment for tyrosinaemia type I: first human experience. JIMD Rep. 2012;5:27-33. doi: 10.1007/8904_2011_88. Epub 2011 Dec 16. PubMed PMID: 23430914; PubMed Central PMCID: PMC3509920.

15: Wisse RP, Wittebol-Post D, Visser G, van der Lelij A. Corneal depositions in tyrosinaemia type I during treatment with Nitisinone. BMJ Case Rep. 2012 Nov 30;2012. pii: bcr2012006301. doi: 10.1136/bcr-2012-006301. PubMed PMID: 23203167; PubMed Central PMCID: PMC4543320.

16: Larochelle J, Alvarez F, Bussières JF, Chevalier I, Dallaire L, Dubois J, Faucher F, Fenyves D, Goodyer P, Grenier A, Holme E, Laframboise R, Lambert M, Lindstedt S, Maranda B, Melançon S, Merouani A, Mitchell J, Parizeault G, Pelletier L, Phan V, Rinaldo P, Scott CR, Scriver C, Mitchell GA. Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Québec. Mol Genet Metab. 2012 Sep;107(1-2):49-54. doi: 10.1016/j.ymgme.2012.05.022. Epub 2012 Jul 13. PubMed PMID: 22885033.

17: Onojafe IF, Adams DR, Simeonov DR, Zhang J, Chan CC, Bernardini IM, Sergeev YV, Dolinska MB, Alur RP, Brilliant MH, Gahl WA, Brooks BP. Nitisinone improves eye and skin pigmentation defects in a mouse model of oculocutaneous albinism. J Clin Invest. 2011 Oct;121(10):3914-23. doi: 10.1172/JCI59372. PubMed PMID: 21968110; PubMed Central PMCID: PMC3223618.

18: Manga P, Orlow SJ. Informed reasoning: repositioning of nitisinone to treat oculocutaneous albinism. J Clin Invest. 2011 Oct;121(10):3828-31. doi: 10.1172/JCI59763. PubMed PMID: 21968107; PubMed Central PMCID: PMC3195484.

19: Introne WJ, Perry MB, Troendle J, Tsilou E, Kayser MA, Suwannarat P, O'Brien KE, Bryant J, Sachdev V, Reynolds JC, Moylan E, Bernardini I, Gahl WA. A 3-year randomized therapeutic trial of nitisinone in alkaptonuria. Mol Genet Metab. 2011 Aug;103(4):307-14. doi: 10.1016/j.ymgme.2011.04.016. Epub 2011 May 6. PubMed PMID: 21620748; PubMed Central PMCID: PMC3148330.

20: Prieto JA, Andrade F, Lage S, Aldámiz-Echevarría L. Comparison of plasma and dry blood spots as samples for the determination of nitisinone (NTBC) by high-performance liquid chromatography-tandem mass spectrometry. Study of the stability of the samples at different temperatures. J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Apr 1;879(11-12):671-6. doi: 10.1016/j.jchromb.2011.01.031. Epub 2011 Feb 2. PubMed PMID: 21377430.