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Predicting tyrosinaemia: a mathematical model of 4-hydroxyphenylpyruvate dioxygenase inhibition by nitisinone in rats

Ward, JP, Dunster, JL, Derks, GLA, Mistry, P and Salazar, JD (2016) Predicting tyrosinaemia: a mathematical model of 4-hydroxyphenylpyruvate dioxygenase inhibition by nitisinone in rats Mathematical Medicine and Biology.

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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.

Item Type: Article
Subjects : subj_Mathematics
Divisions : Faculty of Engineering and Physical Sciences > Mathematics
Authors :
AuthorsEmailORCID
Ward, JPUNSPECIFIEDUNSPECIFIED
Dunster, JLUNSPECIFIEDUNSPECIFIED
Derks, GLAUNSPECIFIEDUNSPECIFIED
Mistry, PUNSPECIFIEDUNSPECIFIED
Salazar, JDUNSPECIFIEDUNSPECIFIED
Date : 15 June 2016
Identification Number : 10.1093/imammb/dqw006
Copyright Disclaimer : © The author 2008. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.
Uncontrolled Keywords : nitisinone, 4-hydroxyphenylpyruvate dioxygenase, tyrosinaemia, rat, mathematical model, PBPK/PD, asymptotic analysis.
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 13 May 2016 17:38
Last Modified : 15 Nov 2016 14:42
URI: http://epubs.surrey.ac.uk/id/eprint/810712

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