期刊
INTERNATIONAL JOURNAL OF PHARMACEUTICS
卷 458, 期 1, 页码 156-168出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijpharm.2013.09.033
关键词
PBPK; MATLAB Simulink (R); Melatonin; Light; Circadian rhythms; Pharmacokinetics
资金
- Applied Research Program 14dm of Defence Research and Development Canada
Physiologically based pharmacokinetic (PBPK) models were developed using MATLAB Simulink (R) to predict diurnal variations of endogenous melatonin with light as well as pharmacokinetics of exogenous melatonin via different routes of administration. The model was structured using whole body, including pineal and saliva compartments, and parameterized based on the literature values for endogenous melatonin. It was then optimized by including various intensities of light and various dosage and formulation of melatonin. The model predictions generally have a good fit with available experimental data as evaluated by mean squared errors and ratios between model-predicted and observed values considering large variations in melatonin secretion and pharmacokinetics as reported in the literature. It also demonstrates the capability and usefulness in simulating plasma and salivary concentrations of melatonin under different light conditions and the interaction of endogenous melatonin with the pharmacokinetics of exogenous melatonin. Given the mechanistic approach and programming flexibility of MATLAB Simulink, the PBPK model could provide predictions of endogenous melatonin rhythms and pharmacokinetic changes in response to environmental (light) and experimental (dosage and route of administration) conditions. Furthermore, the model may be used to optimize the combined treatment using light exposure and exogenous melatonin for maximal phase advances or delays. Crown Copyright (C) 2013 Published by Elsevier B.V. All rights reserved.
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