Novel testing strategy for prediction of rat biliary excretion of intravenously administered estradiol-17β glucuronide

Abstract

The aim of the present study was to develop a generic rat physiologically based kinetic (PBK) model that includes a novel testing strategy where active biliary excretion is incorporated using estradiol-17β glucuronide (E217βG) as the model substance. A major challenge was the definition of the scaling factor for the in vitro to in vivo conversion of the PBK-model parameter Vmax. In vitro values for the Vmax and Km for transport of E217βG were found in the literature in four different studies based on experiments with primary rat hepatocytes. The required scaling factor was defined based on fitting the PBK model-based predicted values to reported experimental data on E217βG blood levels and cumulative biliary E217βG excretion. This resulted in a scaling factor of 129 mg protein/g liver. With this scaling factor the PBK model predicted the in vivo data for blood and cumulative biliary E217βG levels with on average of less than 1.8-fold deviation. The study provides a proof of principle on how biliary excretion can be included in a generic PBK model using primary hepatocytes to define the kinetic parameters that describe the biliary excretion.

Including active excretion in physiologically based kinetic models for new approach methodologies

“…For some compounds the absorption, distribution, metabolism and excretion (ADME) characteristics are substantially influenced by active transport in for example the intestine, kidneys, liver, placenta or the blood-brain-barrier. Incorporating this active transport into physiologically based kinetic (PBK) models based on in vitro data is still in a developing stage (Kasteel et al 2021;Noorlander et al 2021a;Noorlander et al 2021b;Noorlander et al 2022;Poirier et al 2009;Strikwold et al 2017b;Worley and Fisher 2015). The challenges related to incorporation of active transport are for example the type of in vitro models to be used to quantify the kinetics of the active transporters involved and the scaling factors needed to translate in vitro obtained data to the in vivo situation.…”