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Title: Predicting tyrosinaemia: a mathematical model of 4-hydroxyphenylpyruvate dioxygenase inhibition by nitisinone in rats
Authors: Ward, John P.
Dunster, Joanne L.
Derks, Gianne
Mistry, Pratibha
Salazar, Jose D.
Keywords: Nitisinone
4-hydroxyphenylpyruvate dioxygenase
Tyrosinaemia
Rats
Mathematical model
PBPK/PD
Asymptotic analysis
Issue Date: 2016
Publisher: Oxford University Press (© Institute of Mathematics and its Applications)
Citation: WARD, J. ... et al., 2016. Predicting tyrosinaemia: a mathematical model of 4-hydroxyphenylpyruvate dioxygenase inhibition by nitisinone in rats. Mathematical Medicine and Biology [in press].
Abstract: Nitisinone or 2-(2-nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione, is a reversible inhibitor of 4- hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme important in tyrosine catabolism. Today, nitisinone is successfully used to treat Hereditary Tyrosinaemia type 1, although its original expected role was as a herbicide. In laboratory animals, treatment with nitisinone leads to the elevation of plasma tyrosine (tyrosinaemia). In rats and Beagle dogs, repeat low-dose exposure to nitisinone leads to corneal opacities whilst similar studies in the mouse and Rhesus monkey showed no comparable toxicities or other treatment related findings. The differences in toxicological sensitivities have been related to the upper limit of the concentration of tyrosine that accumulates in plasma, which is driven by the amount/activity of tyrosine aminotransferase. A physiologically based, pharmacodynamics ordinary differential equation model of HPPD inhibition to bolus exposure of nitisinone in vivo is presented. Going beyond traditional approaches, asymptotic analysis is used to separate the different timescales of events involved in HPPD inhibition and tyrosinaemia. This analysis elucidates, in terms of the model parameters, a critical inhibitor concentration (at which tyrosine concentration starts to rise) and highlights the contribution of in vitro measured parameters to events in an in vivo system. Furthermore, using parameter-fitting methods, a systematically derived reduced model is shown to fit well to rat data, making explicit how the parameters are informed by such data. This model in combination with in vitro descriptors has potential as a surrogate for animal experimentation to predict tyrosinaemia, and further development can extend its application to other related medical scenarios.
Description: This item will remain Closed Access until 12 months after the date of its commercial publication.
Version: Accepted for publication
URI: https://dspace.lboro.ac.uk/2134/21361
Publisher Link: http://imammb.oxfordjournals.org/
ISSN: 1477-8599
Appears in Collections:Closed Access (Maths)

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