How predictive are isolated perfused liver data of hepatic clearance? A meta-analysis of isolated perfused rat liver data.

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 (). However, to date, IPRL data has not been evaluated for prediction accuracy.In addition to a detailed overview of available IPRL literature, we present an in-depth analysis of the performance of IPRL in prediction.

Proof of Concept of an All-in-One System for Measuring Hepatic Influx, Egress, and Metabolic Clearance Based on the Extended Clearance Concept.

Hepatic clearance ( ) prediction is a critical parameter to estimate human dose. However, underpredictions are common, especially for slowly metabolized drugs, and may be attributable to drug properties that pose challenges for conventional in vitro absorption, distribution, metabolism, and elimination (ADME) assays, resulting in nonvalid data, which prevents in vitro to in vivo extrapolation and predictions. Other processes, including hepatocyte and biliary distribution via transporters, can also play significant roles in Recent advances in understanding the interplay of metabolism and drug transport for clearance processes have aided in developing the extended clearance model.

Optimization, Characterization, and Comparison of Two Luciferase-Expressing Mouse Glioblastoma Models.

Glioblastoma (GBM) is the most aggressive brain cancer. To model GBM in research, orthotopic brain tumor models, including syngeneic models like GL261 and genetically engineered mouse models like TRP, are used. In longitudinal studies, tumor growth and the treatment response are typically tracked with in vivo imaging, including bioluminescence imaging (BLI), which is quick, cost-effective, and easily quantifiable.

Assumptions Underlying Hepatic Clearance Models: Recognizing the Influence of Saturable Protein Binding on Driving Force Concentration and Discrimination Between Models of Hepatic Clearance.

One underlying assumption of hepatic clearance models is often underappreciated. Namely, plasma protein binding is assumed to be nonsaturable within a given drug concentration range, dependent only on protein concentration and equilibrium dissociation constant. However, in vitro hepatic clearance experiments often use low albumin concentrations that may be prone to saturation effects, especially for high-clearance compounds, where the drug concentration changes rapidly.