Multiscale modelling of drug transport and metabolism in liver spheroids.

Autor:	Leedale JA; EPSRC Liverpool Centre for Mathematics in Healthcare, Department of Mathematical Sciences, University of Liverpool, Liverpool L69 7ZL, UK., Kyffin JA; Department of Applied Mathematics, Liverpool John Moores University, Liverpool L3 3AF, UK., Harding AL; School of Clinical Dentistry, University of Sheffield, Claremont Crescent, Sheffield S10 2TA, UK., Colley HE; School of Clinical Dentistry, University of Sheffield, Claremont Crescent, Sheffield S10 2TA, UK., Murdoch C; School of Clinical Dentistry, University of Sheffield, Claremont Crescent, Sheffield S10 2TA, UK., Sharma P; MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GE, UK., Williams DP; AstraZeneca, IMED Biotech Unit, Drug Safety and Metabolism, Cambridge Science Park, Cambridge CB4 0FZ, UK., Webb SD; EPSRC Liverpool Centre for Mathematics in Healthcare, Department of Mathematical Sciences, University of Liverpool, Liverpool L69 7ZL, UK.; Department of Applied Mathematics, Liverpool John Moores University, Liverpool L3 3AF, UK., Bearon RN; EPSRC Liverpool Centre for Mathematics in Healthcare, Department of Mathematical Sciences, University of Liverpool, Liverpool L69 7ZL, UK.
Jazyk:	angličtina
Zdroj:	Interface focus [Interface Focus] 2020 Apr 06; Vol. 10 (2), pp. 20190041. Date of Electronic Publication: 2020 Feb 14.
DOI:	10.1098/rsfs.2019.0041
Abstrakt:	In early preclinical drug development, potential candidates are tested in the laboratory using isolated cells. These in vitro experiments traditionally involve cells cultured in a two-dimensional monolayer environment. However, cells cultured in three-dimensional spheroid systems have been shown to more closely resemble the functionality and morphology of cells in vivo . While the increasing usage of hepatic spheroid cultures allows for more relevant experimentation in a more realistic biological environment, the underlying physical processes of drug transport, uptake and metabolism contributing to the spatial distribution of drugs in these spheroids remain poorly understood. The development of a multiscale mathematical modelling framework describing the spatio-temporal dynamics of drugs in multicellular environments enables mechanistic insight into the behaviour of these systems. Here, our analysis of cell membrane permeation and porosity throughout the spheroid reveals the impact of these properties on drug penetration, with maximal disparity between zonal metabolism rates occurring for drugs of intermediate lipophilicity. Our research shows how mathematical models can be used to simulate the activity and transport of drugs in hepatic spheroids and in principle any organoid, with the ultimate aim of better informing experimentalists on how to regulate dosing and culture conditions to more effectively optimize drug delivery. Competing Interests: We declare we have no competing interests. (© 2020 The Authors.)
Databáze:	MEDLINE
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