About this webinar
For a half-century clearance concepts have been utilized in pharmacokinetics to understand the relationship between the dose administered and the time-course of systemic concentrations. Here we counter the hypothesis that organ clearance determined as hepatic blood flow multiplied by the extraction ratio is model-independent. This hypothesis ignores the fact that for the same steady-state entering and exiting concentrations, exposure within the liver is not the same for different models of hepatic elimination, and in pharmacokinetics clearance has always been determined as the amount of drug eliminated divided by the exposure (integrated systemic concentrations) driving that elimination. An extensive review of all experimental isolated perfused rat liver data indicates that there are no experimental results that unambiguously demonstrate that the data are reasonably best fit by the parallel tube or axial dispersion models. In contrast, there are experimental results showing that the data fit only the well-stirred model. This difference in interpretation is not just an academic argument. It affects the ability to obtain accurate IVIVE determinations; it is an unrecognized component of albumin mediated hepatic uptake analyses; it is important in determining Kpuu relevance; and in PBPK program validity, among others. Clearance is always model dependent.
- Understand the basis for the definition and calculation of clearance when systemic concentrations are measured and when calculated for an isolated perfused organ
- Understand the relevance and limitations of the various models of hepatic drug elimination(i.e, well-stirred; parallel tube and axial dispersion)
- Become familiar with the experimental data that attempts to differentiate the models of hepatic elimination for isolated perfused organ studies.