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Pharmacokinetics and pharmacodynamics of NTBC (2‐(2‐nitro‐4‐fluoromethylbenzoyl)‐1,3‐cyclohexanedione) and mesotrione, inhibitors of 4‐hydroxyphenyl pyruvate dioxygenase (HPPD) following a single dose to healthy male volunteers
Open accessAbstract
Aims NTBC (2‐(2‐nitro‐4‐fluoromethylbenzoyl)‐1,3‐cyclohexanedione) and mesotrione (2‐(4‐methylsulphonyl‐2‐nitrobenzoyl)‐1,3‐cyclohexanedione) are inhibitors of 4‐hydroxyphenyl pyruvate dioxygenase (HPPD). NTBC has been successfully used as a treatment for hereditary tyrosinaemia type 1 (HT‐1), while mesotrione has been developed as an herbicide. The pharmacokinetics of the two compounds were investigated in healthy male volunteers following single oral administration. The aim of the NTBC study was to assess the bioequivalence of two different formulations and to determine the extent of the induced tyrosinaemia. The mesotrione study was performed to determine the magnitude and duration of the effect on tyrosine catabolism. Additionally, the urinary excretion of unchanged mesotrione was measured to assess the importance of this route of clearance and to help develop a strategy for monitoring occupational exposure. Methods A total of 28 volunteers participated in two separate studies with the compounds. In the first study, the relative bioavailability of NTBC from liquid and capsule formulations was compared and the effect on plasma tyrosine concentrations measured. In the second study the pharmacokinetics of mesotrione were determined at three doses. Plasma tyrosine concentrations were monitored and the urinary excretion of mesotrione and tyrosine metabolites was measured. Results Both compounds were well tolerated at the dose levels studied. Peak plasma concentrations of NTBC were rapidly attained following a single oral dose of 1 mg kg−1 body weight of either formulation and the half‐life in plasma was approximately 54 h. There were no statistical differences in mean (± s.d.) AUC(0,∞) (capsule 602 ± 154 vs solution 602 ± 146 µg ml−1 h) or t½ (capsule 55 ± 13 vs solution 54 ± 8 h) and these parameters supported the bioequivalence of the two formulations. Mesotrione was also rapidly absorbed, with a significant proportion of the dose eliminated unchanged in urine. The plasma half‐life was approximately 1 h and was independent of dose and AUC(0,∞) and Cmax increased linearly with dose. Following administration of 1 mg NTBC kg−1 in either formulation, the concentrations of tyrosine in plasma increased to approximately 1100 nmol ml−1. Concentrations were still approximately 8 times those of background at 14 days after dosing, but had returned to background levels within 2 months of the second dose. Administration of mesotrione resulted in an increase in tyrosine concentrations which reached a maximum of approximately 300 nmol ml−1 following a dose of 4 mg kg−1 body weight. Concentrations returned to those of background within 2 days of dosing. Urinary excretion of tyrosine metabolites was increased during the 24 h immediately following a dose of 4 mg mesotrione kg−1, but returned to background levels during the following 24 h period. Conclusions NTBC and mesotrione are both inhibitors of HPPD, although the magnitude and duration of their effect on tyrosine concentrations are very different. When normalized for dose, the extent of the induced tyrosinaemia after administration of NTBC and over the duration of these studies, was approximately 400 fold greater than that following administration of mesotrione. The persistent and significant effect on HPPD following administration of NTBC make it suitable for the treatment of patients with hereditary tyrosinaemia type 1 (HT‐1), whilst the minimal and transient effects of mesotrione minimize the likelihood of a clinical effect in the event of systemic exposure occurring during occupational use.
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“Random sampling is possible as NTBC has a long half-life of 54 h [50].”
From Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice (2014) · cites this paper as [50]
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“start nitisinone (NTBC, Orfadin®,) in a dose of 1 mg/kg/d once a day as the half life is 54 hrs [19,20].”
From Recommendations for the management of tyrosinaemia type 1 (2013) · cites this paper as [19]
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“Because the NTBC half life is known to be 54 hours (Hall et al 2001), we measured the plasma NTBC concentrations in a total of nine patients who were given NTBC as a single daily dose: seven patients were changed frommultiple daily doses to a single dose and two patients were started on a single…”
MethodResultNitisinone for the treatment of hereditary tyrosinemia type I
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“This contrasts with previous studies that indicated NTBC had a stability of at least 24 h in HT1 patients, while in healthy adults even a half-life of 54 h was found (Schlune et al 2012, Hall et al 2001).”
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“These results could be specifically due to the catabolism of Leu to HMB, since Leu-induced suppression of protein degradation was blocked by the pre-incubation with mesotrione, a specific inhibitor of KICD [40].”
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A Perspective on the Phytopharmaceuticals Responsible for the Therapeutic Applications
Joshi, R. K. (2016) · Advances in medical technologies and clinical practice book series · doi:10.4018/978-1-5225-0754-3.ch008 · Cited by 6
Plant Metabolites as New Leads to Drug Discovery
Sasidharan, S., & Saudagar, P. (2019) · Springer eBooks · doi:10.1007/978-981-13-7205-6_12 · Cited by 6
Deployment and transcriptional evaluation of nitisinone, an FDA ‐approved drug, to control bed bugs
Sterkel, M., Tompkin, J., Schal, C., Guerra, L. R. M., Pessoa, G. C. D., de Oliveira, P. L., & Benoit, J. B. (2025) · Pest Management Science · doi:10.1002/ps.8614 · Cited by 5
Guffon, N., Bröijersén, A., Palmgren, I., Rudebeck, M., & Olsson, B. (2017) · JIMD Reports · doi:10.1007/8904_2017_29 · Cited by 5
“Although 1 mg/kg body weight per day divided in two daily doses is presently recommended (Orfadin® summary of product characteristics), once-daily dosing is supported by the long half-life of nitisinone in plasma (median approximately 54 h ¼ 2.3 days) (Hall et al. 2001).”
BackgroundInfluentialCartwright, J., & Green, R. M. (2010) · Veterinary Clinical Pathology · doi:10.1111/j.1939-165x.2010.00231.x · Cited by 5
Current management options for tyrosinemia
El-Shabrawi, M. H. F., & Kamal (2013) · Orphan Drugs Research and Reviews · doi:10.2147/odrr.s31501 · Cited by 5
“80,81 Based on the fact that the half-life of NTBC is known to be 54 hours, 82 Schlune et al, 19 used a single daily dose regimen in their patients, and they suggested that a single daily dose is as effective as the two daily doses and that it improves adherence.”
Fawole, O. A. (2009) · ResearchSpace (University of KwaZulu-Natal) · Cited by 5
Gryff‐Keller, A., Szczeciński, P., & Kraska‐Dziadecka, A. (2010) · Journal of Physical Organic Chemistry · doi:10.1002/poc.1736 · Cited by 4
Yeo, M., Turner, C., Dalton, N. R., Rahman, Y., & Vara, R. (2020) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/0004563220961760 · Cited by 4
Gobinath, P., Packialakshmi, P., Ali, D., Alarifi, S. A., Gurusamy, R., Idhayadhulla, A., & Surendrakumar, R. (2022) · BioMed Research International · doi:10.1155/2022/7228259 · Cited by 4
“2-cyclohexanedione, one of these herbicides, is so selective and effective that it causes tyrosinemia [26] shown in Figure 3.”
RetractedPecquet, A. M., Bridgwood, K., Cowie, D., Hofstra, A. H., Wu, Y., Whalley, S., & Webb, S. D. (2024) · Critical Reviews in Toxicology · doi:10.1080/10408444.2024.2353174 · Cited by 4
“In brief, mammalian HPPD inhibition blocks tyrosine catabolism resulting in an increase in systemic tyrosine levels (Hall et al. 2001).”
InfluentialDisorders of Tyrosine Metabolism
Chakrapani, A., Gissen, P., & McKiernan, P. J. (2016) · Springer eBooks · doi:10.1007/978-3-662-49771-5_17 · Cited by 4
Kaikabo, A. A. (2010) · UpSpace Institutional Repository (University of Pretoria) · Cited by 4
Heme as an initial treatment for severe decompensation in tyrosinemia type 1
Neeleman, R. A., Wilson, J. H. P., Williams, M., & Langendonk, J. G. (2019) · Genetics in Medicine · doi:10.1038/s41436-019-0658-z · Cited by 4
Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasisPreprint
Sterkel, M., Haines, L. R., Casas-Sánchez, A., Adung’a, V. O., Vionette-Amaral, R. J., Quek, S., Rose, C., dos Santos, M. S., Escude, N. G., Ismail, H. M., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.06.08.139808 · Cited by 4
“The NTBC half-life in human plasma is 54 hours [17], so assuming linear drug degradation, human blood would remain toxic to tsetse for at least a week after a single therapeutic dose.”
BackgroundInfluentialOverview of European Practices for Management of Tyrosinemia Type 1: Towards European Guidelines
Dijkstra, A. M., Das, A. M., Maiorana, A., Heiner-Fokkema, M. R., & van Spronsen, F. J. (2025) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.70089 · Cited by 6
A stability indicating HPLC method for the determination of nitisinone in capsules
Souri, E., Lahiji, F., Nourhashemi, T., & Jalalizadeh, H. (2015) · Indian Journal of Pharmaceutical Sciences · doi:10.4103/0250-474x.159674 · Cited by 3
“Only a few articles have been published which reported the HPLC determination of nitisinone in biological fluids[2,3].”
BackgroundBiochemical and behavioural profile of NTBC treated Tyrosinemie type 1 mice
van Ginkel, W. G., Winn, S. R., Dudley, S., Krenik, D., Perez, R., Rimann, N., Thöny, B., Raber, J., & Harding, C. O. (2022) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2022.07.001 · Cited by 2
Drug Discovery From Natural Sources
Chin, Y., Balunas, M. J., Chai, H. B., & Kinghorn, A. D. (2008) · Springer eBooks · doi:10.1007/978-0-387-76678-2_2 · Cited by 4
Curtis, S., Norman, B. P., Milan, A. M., Gallagher, J. A., Olsson, B., Ranganath, L. R., & Roberts, N. B. (2019) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2019.06.010 · Cited by 3
Herbicides with Bleaching Properties
Krämer, W., & Schirmer, U. (2007) · doi:10.1002/9783527619580.ch4 · Cited by 3
Pharmacological Therapy in Inborn Errors of Metabolism
Das, A. M., & Illsinger, S. (2018) · Springer eBooks · doi:10.1007/978-3-319-56637-5_62-1 · Cited by 2
A Perspective on the Phytopharmaceuticals Responsible for the Therapeutic Applications
Joshi, R. K. (2016) · IGI Global eBooks · doi:10.4018/978-1-5225-1762-7.ch017 · Cited by 2
Successive Drug Therapy for a Very Rare Autosomal Diseases
Al-Noaemi, M. C., & Daghriri, H. A. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.89583 · Cited by 2
“The standard recommended dosage of NTBC is 1 mg/kg body weight [43, 59, 60].”
BackgroundRamirez, M. A. V., Sterkel, M., Martins, A. J., Lima, J. B. P., & de Oliveira, P. L. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/669747 · Cited by 2
A Review of Metabolic Disorder of Amino Acid Tyrosinemia type I: When to Suspect and how to Diagnose
Alobaidy, H. (2017) · IOSR Journal of Pharmacy and Biological Sciences · doi:10.9790/3008-1202015664 · Cited by 1
“Treatment with Nitisinone (NTBC) (2-(2-nitro-4fluoromethylbenzoyl)-1,3-cyclohexanedione)) can prevent liver, kidney, and neurological symptoms if started immediately [11, 12, 13, 14, 15, 16,17].”
BackgroundNitisinone use in hereditary tyrosinemia and alkaptonuria
Introne, W. J., O’Brien, K., & Gahl, W. A. (2010) · Cambridge University Press eBooks · doi:10.1017/cbo9780511777905.010 · Cited by 1
COMPARATIVE STUDY OF OCIMUM SANCTUM OIL AND ANTIMALARIAL TABLETS CONTAINING CHLOROQUINE PHOSPHATE
Kulshreshtha, P., Kulshrestha, S., Rathor, N., & Shukla, R. N. (2014) · International Research Journal of Pharmacy · doi:10.7897/2230-8407.050341 · Cited by 1
Ward, J., Dunster, J. L., Derks, G., Mistry, P., & Salazar, J. D. (2016) · Mathematical Medicine and Biology A Journal of the IMA · doi:10.1093/imammb/dqw006 · Cited by 1
“• Normal tyrosine concentration measurements in the blood are available for mice, rats and humans (Hall et al. (2001) and references below).”
BackgroundA simple RP-HPLC method for determination of nitisinone in pharmaceuticals
Mustafa, Z., Arsova‐Sarafinovska, Z., Shishovska, M. A., & Grozdanova, A. (2019) · Macedonian Pharmaceutical Bulletin · doi:10.33320/10.33320/maced.pharm.bull.2019.65.02.007 · Cited by 1
Metadata
- Authors
- Hall, M. G., Wilks, M. F., Provan, W. M., Eksborg, S., & Lumholtz, B.
- Affiliations
- Zeneca Central Toxicology Laboratory (GB)
- Karolinska University Hospital (SE)
- Swedish Orphan Biovitrum (Sweden) (SE)
- Venue
- British Journal of Clinical Pharmacology
- Publisher
- Wiley
- Published
- 2001-08
- Volume
- 52
- Issue
- 2
- Pages
- 169-177
- ISSN
- 0306-5251 (ISSN-L)
- 1365-2125
- PMC
- PMC2014534
- OpenAlex
- W1510018222
- Cited by
- 110
- References
- 12
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 2 · 2020: 8 · 2019: 10 · 2018: 3 · 2017: 10 · 2016: 6 · 2015: 5 · 2014: 3 · 2013: 6 · 2012: 2
- FWCI
- 1.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Clinical Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pesticide Exposure and Toxicity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- NTBC, mesotrione, pharmacokinetics, pharmacodynamics, bioequivalence, relative bioavailability, plasma tyrosine, urinary excretion, tyrosine catabolism, herbicides, single oral dose, healthy volunteers, occupational exposure monitoring
- MeSH terms
- Administration, Oral, Chemistry, Pharmaceutical, Cyclohexanones, Enzyme Inhibitors, Half-Life, Humans, Male, Nitrobenzoates, Therapeutic Equivalency, Tyrosine, 4-Hydroxyphenylpyruvate Dioxygenase, Area Under Curve, Tyrosinemias
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