TY - JOUR
T1 - Quantitative Kinetic Models from Intravital Microscopy
T2 - A Case Study Using Hepatic Transport
AU - Tavakoli, Meysam
AU - Tsekouras, Konstantinos
AU - Day, Richard
AU - Dunn, Kenneth W.
AU - Pressé, Steve
N1 - Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/5/19
Y1 - 2019/5/19
N2 - The liver performs critical physiological functions, including metabolizing and removing substances, such as toxins and drugs, from the bloodstream. Hepatotoxicity itself is intimately linked to abnormal hepatic transport, and hepatotoxicity remains the primary reason drugs in development fail and approved drugs are withdrawn from the market. For this reason, we propose to analyze, across liver compartments, the transport kinetics of fluorescein - a fluorescent marker used as a proxy for drug molecules - using intravital microscopy data. To resolve the transport kinetics quantitatively from fluorescence data, we account for the effect that different liver compartments (with different chemical properties) have on fluorescein's emission rate. To do so, we develop ordinary differential equation transport models from the data where the kinetics is related to the observable fluorescence levels by "measurement parameters" that vary across different liver compartments. On account of the steep non-linearities in the kinetics and stochasticity inherent to the model, we infer kinetic and measurement parameters by generalizing the method of parameter cascades. For this application, the method of parameter cascades ensures fast and precise parameter estimates from noisy time traces.
AB - The liver performs critical physiological functions, including metabolizing and removing substances, such as toxins and drugs, from the bloodstream. Hepatotoxicity itself is intimately linked to abnormal hepatic transport, and hepatotoxicity remains the primary reason drugs in development fail and approved drugs are withdrawn from the market. For this reason, we propose to analyze, across liver compartments, the transport kinetics of fluorescein - a fluorescent marker used as a proxy for drug molecules - using intravital microscopy data. To resolve the transport kinetics quantitatively from fluorescence data, we account for the effect that different liver compartments (with different chemical properties) have on fluorescein's emission rate. To do so, we develop ordinary differential equation transport models from the data where the kinetics is related to the observable fluorescence levels by "measurement parameters" that vary across different liver compartments. On account of the steep non-linearities in the kinetics and stochasticity inherent to the model, we infer kinetic and measurement parameters by generalizing the method of parameter cascades. For this application, the method of parameter cascades ensures fast and precise parameter estimates from noisy time traces.
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U2 - 10.1021/acs.jpcb.9b04729
DO - 10.1021/acs.jpcb.9b04729
M3 - Article
C2 - 31298856
AN - SCOPUS:85071668672
SN - 1520-6106
VL - 123
SP - 7302
EP - 7312
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 34
ER -