Quantitative Kinetic Models from Intravital Microscopy: A Case Study Using Hepatic Transport

Meysam Tavakoli, Konstantinos Tsekouras, Richard Day, Kenneth W. Dunn, Steve Pressé

Research output: Contribution to journalArticle

Abstract

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hepatic transport, and hepatotoxicity remains the primary reason drugs in development fail and approved drugs are withdrawn from the market.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.

Original languageEnglish (US)
JournalJournal of Physical Chemistry B
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

liver
Liver
microscopy
drugs
compartments
Kinetics
kinetics
Pharmaceutical Preparations
cascades
Fluorescence
fluorescence
Fluorescein
Ordinary differential equations
chemical properties
markers
Chemical properties
differential equations
nonlinearity
Intravital Microscopy
Molecules

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

Cite this

Quantitative Kinetic Models from Intravital Microscopy : A Case Study Using Hepatic Transport. / Tavakoli, Meysam; Tsekouras, Konstantinos; Day, Richard; Dunn, Kenneth W.; Pressé, Steve.

In: Journal of Physical Chemistry B, 01.01.2019.

Research output: Contribution to journalArticle

Tavakoli, Meysam ; Tsekouras, Konstantinos ; Day, Richard ; Dunn, Kenneth W. ; Pressé, Steve. / Quantitative Kinetic Models from Intravital Microscopy : A Case Study Using Hepatic Transport. In: Journal of Physical Chemistry B. 2019.
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