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.
Highlights
The kinetic profile of a substance is of importance when considering human safety assessment and drug development
Prediction of these kinetic profiles based on absorption, distribution, metabolism and excretion (ADME) using physiologically based kinetic (PBK) modelling has been shown of value to predict blood levels of drugs following defined dose levels in forward dosimetry, and in socalled reverse dosimetry for quantitative in vitro—in vivo extrapolation (QIVIVE) (Louisse et al 2017; Rietjens et al 2011)
It is of importance to note that main deviations between predicted and observed in vivo data could be related to especially differences between reported experimental data at the same dose level
Summary
The kinetic profile of a substance is of importance when considering human safety assessment and drug development. There already have been studies on QIVIVE using PBK-modelling focussing on especially excretion of certain drugs via active transport from the liver to the bile (Chapy et al 2015; Jamei et al 2014; Jones et al 2012). Both endogenous and exogenous glucuronide conjugates have been shown to be actively excreted via this route (Cronholm et al 1971; Ge et al 2016; Hjelle and Klaassen 1984). The common properties of the compounds for which this active transport from liver into bile was shown important are that they have a low membrane permeability, a molecular weight cut off of 475 Da (400 Da for rats), remain mostly unchanged and are excreted via active uptake and efflux in and from the liver cells into bile (Yang et al 2009)
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