How predictive are isolated perfused liver data of <i>in vivo</i> hepatic clearance? A meta-analysis of isolated perfused rat liver data
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Isolated perfused rat liver (IPRL) experiments have been used to answer clearance-related questions, including evaluating the impact of pathological and physiological processes on hepatic clearance (<i>CL<sub>H</sub></i>). However, to date, IPRL data has not been evaluated for <i>in vivo CL<sub>H</sub></i> prediction accuracy.In addition to a detailed overview of available IPRL literature, we present an in-depth analysis of the performance of IPRL in <i>CL<sub>H</sub></i> prediction.While the entire dataset poorly predicted <i>CL<sub>H</sub></i> (GAFE = 3.2; 64% within 3-fold), IPRL conducted under optimal experimental conditions, such as in the presence of plasma proteins and with a perfusion rate within 2-fold of physiological liver blood flow and corrected for unbound fraction in the presence of red blood cells, can accurately predict rat <i>CL<sub>H</sub></i> (GAFE = 2.0; 78% within 3-fold). Careful consideration of experimental conditions is needed to allow proper data analysis.Further, isolated perfused liver experiments in other species, including human livers, may allow us to address the current <i>in vitro</i>-<i>in vivo</i> disconnects of hepatic metabolic clearance and improve our methodology for <i>CL<sub>H</sub></i> predictions. Isolated perfused rat liver (IPRL) experiments have been used to answer clearance-related questions, including evaluating the impact of pathological and physiological processes on hepatic clearance (<i>CL<sub>H</sub></i>). However, to date, IPRL data has not been evaluated for <i>in vivo CL<sub>H</sub></i> prediction accuracy. In addition to a detailed overview of available IPRL literature, we present an in-depth analysis of the performance of IPRL in <i>CL<sub>H</sub></i> prediction. While the entire dataset poorly predicted <i>CL<sub>H</sub></i> (GAFE = 3.2; 64% within 3-fold), IPRL conducted under optimal experimental conditions, such as in the presence of plasma proteins and with a perfusion rate within 2-fold of physiological liver blood flow and corrected for unbound fraction in the presence of red blood cells, can accurately predict rat <i>CL<sub>H</sub></i> (GAFE = 2.0; 78% within 3-fold). Careful consideration of experimental conditions is needed to allow proper data analysis. Further, isolated perfused liver experiments in other species, including human livers, may allow us to address the current <i>in vitro</i>-<i>in vivo</i> disconnects of hepatic metabolic clearance and improve our methodology for <i>CL<sub>H</sub></i> predictions.
