Modeling and Inference of Hepatic Transport Kinetics

The liver performs critical physiological functions, including metabolizing and removing substances such as toxins and medications from the bloodstream. Intravital microscopy (IVM) has developed into a versatile tool to monitor hepatic transport kinetics and its data is poised to provide greater insight into hepatotoxicity. Hepatotoxicity itself is intimately linked to abnormal hepatic transport and liver injuries remain the primary reason drugs in development fail and approved drugs are withdrawn from the market. Here we propose new tools to learn, from IVM data, transport kinetics of fluorescein across liver compartments which, due to their chemical composition, differentially impact fluorescein’s emission properties. We propose a way by which IVM data may be turned into a quantitative differential equation transport model by introducing fluorophore “visibility parameters" across different regions that we infer jointly alongside transport rates (kinetic parameters). To perform the parameter inference, we adapt the method of parameter cascades which ensures fast and precise parameter estimates from noisy time traces under conditions of curve smoothness. We test our approach on both synthetic data and apply our method to experimental data.