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Clearance is driven by exposure and is always model dependent

Description

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.

Learning Objectives

  • 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.
Moderated by Hartmut Derendorf, PhD

Contributors

  • Leslie Benet, Ph.D.

    Dr. Benet, Professor and former Chairman (1978-1998) of Bioengineering and Therapeutic Sciences, University of California San Francisco (UCSF), received his AB, BS and MS from the University of Michigan, and Ph.D. from UCSF. He has received eight honorary doctorates, four from Europe and four from the US, most recently the Catholic University of Leuven (2010) and the University of Michigan (2011). Dr. Benet served as President of the Academy of Pharmaceutical Sciences (1985) and in 1986 was a founder and first President of the American Association of Pharmaceutical Scientists. In 1987 he was elected to membership in the Institute of Medicine of the US National Academy of Sciences. In 1993-4 he served as President of the American Association of Colleges of Pharmacy, from 1996-2000 as Chair of the International Pharmaceutical Federation (FIP) Board of Pharmaceutical Sciences and from 2006-2012 as Chair of the FIP Foundation for Education and Research.

    Most recently among his many honors were the Hunter Award in Therapeutics from the American Society for Clinical Pharmacology and Therapeutics (2010), the Distinguished Investigator Award of the American College of Clinical Pharmacology (2011), Honorary Membership in FIP (2012), dedication of the September 2012 issue of Pharmaceutical Research, the 2013 APhA Ebert Prize, dedication of the September 2013 issue of Journal of Pharmaceutical Sciences, selection for the 2013 AAPS Journal Manuscript Award and the FDA/ASCPT Abrams Lecturer in 2015. Dr. Benet has published over 540 scientific articles and book chapters, holds 12 patents and served as editor of 7 books. He is one of only 16 scientists listed by Thompson Reuters in both 2001 and 2014 among the most highly cited pharmacologists worldwide with his peer reviewed publications being referenced on more than 22,000 occasions.

May 14, 2020
Thu 12:30 PM EDT

Duration 1H 30M

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