Predicting tyrosinaemia: a mathematical model of 4-hydroxyphenylpyruvate dioxygenase inhibition by nitisinone in rats.
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.
Department of Mathematical Sciences, Loughborough University, Loughborough LE11 3TU, UK.
John P
JP
Ward
Department of Mathematics & Statistics, University of Reading, Reading RG6 6AX, UK.
Joanne L
JL
Dunster
Department of Mathematics, University of Surrey, Guildford GU2 7XH, UK.
Gianne
G
Derks
Product Safety, Syngenta, Jealott's Hill International Research Centre, Bracknell RG42 6EY, UK.
Pratibha
P
Mistry
Product Safety, Syngenta, Jealott's Hill International Research Centre, Bracknell RG42 6EY, UK.
José D
JD
Salazar
D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D003198:Computer Simulation; D003512:Cyclohexanones / Q000008:administration & dosage / Q000009:adverse effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D055641:Mathematical Concepts; D023421:Models, Animal; D008954:Models, Biological; D009579:Nitrobenzoates / Q000008:administration & dosage / Q000009:adverse effects*; D051381:Rats; D014443:Tyrosine / Q000378:metabolism; D020176:Tyrosinemias / Q000209:etiology* / Q000378:metabolism
D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D009579:Nitrobenzoates; D014443:Tyrosine; D015111:4-Hydroxyphenylpyruvate Dioxygenase; C077073:nitisinone
4-hydroxyphenylpyruvate dioxygenase; PBPK/PD; asymptotic analysis; mathematical model; rat; tyrosinaemia