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

TL;DR

This paper develops a quantitative modeling approach using intravital microscopy data to analyze hepatic transport kinetics of fluorescein, aiding understanding of drug metabolism and hepatotoxicity.

Contribution

It introduces a novel method combining ordinary differential equations and parameter cascades to accurately infer transport kinetics from noisy fluorescence data.

Findings

Effective modeling of fluorescein transport in liver compartments

Fast and precise parameter inference from noisy data

Insights into hepatic transport mechanisms

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hepatic transport and hepatotoxicity remains the primary reason drugs in development fail and approved drugs are withdrawn from the market.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