Leiden University Scholarly Publications

Vendel, E. (2019)

Prediction of spatial-temporal brain drug distribution with a novel mathematical model

Doctoral Thesis

A novel mathematical model describes spatial-temporal drug distribution within one or more brain units, which are cubic representations of a piece of brain tissue with brain capillaries at the edges. The brain unit can be considered a highly representative building block of the brain in terms of drug distribution. While the focus of the model is on drug distribution within the brain ECF, the model includes descriptions of drug concentrations within the blood plasma, drug distribution via brain capillary blood flow, drug transport across the blood-brain barrier (BBB) by passive paracellular and transcellular transport as well as active transport, brain ECF diffusion, brain ECF bulk flow, non-specific binding of the drug to brain tissue, and drug target binding kinetics. We study the model with analytical methods and numerical simulations. This allows us to examine the integrated effect of the individual processes important to drug distribution and effect on the local concentration...Show moreA novel mathematical model describes spatial-temporal drug distribution within one or more brain units, which are cubic representations of a piece of brain tissue with brain capillaries at the edges. The brain unit can be considered a highly representative building block of the brain in terms of drug distribution. While the focus of the model is on drug distribution within the brain ECF, the model includes descriptions of drug concentrations within the blood plasma, drug distribution via brain capillary blood flow, drug transport across the blood-brain barrier (BBB) by passive paracellular and transcellular transport as well as active transport, brain ECF diffusion, brain ECF bulk flow, non-specific binding of the drug to brain tissue, and drug target binding kinetics. We study the model with analytical methods and numerical simulations. This allows us to examine the integrated effect of the individual processes important to drug distribution and effect on the local concentration-time profiles of free and (non-)specifically bound drug. Moreover, the model allows us to generate a local distribution profile of a drug within the brain. In addition, the impact of disease-induced changes in brain-specific properties on the concentrations of drug within the brain ECF is assessed.Show less

Mathematical model

Drug distribution

Brain extracellular fluid

Drug binding

Drug transport

Pharmacokinetics

All authors

Vendel, E.

Supervisor

Merks, R.M.H.; Lange, E.C.M. de

Co-supervisor

Rottschäfer, V.

Committee

Vaart, A.W. van der; Doelman, A.; Derks, G.; Nicholson, C.

Qualification

Doctor (dr.)

Awarding Institution

Mathematical Institute, Science, Leiden

Date

2019-12-17

ISBN (print)

9789402817959