| Autor: |
Pang KS; Leslie Dan Faculty of Pharmacy, University of Toronto, Ontario, Canada (K.S.P., W.I.L.) and Department of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands (G.J.M.) ks.pang@utoronto.ca., Lu WI; Leslie Dan Faculty of Pharmacy, University of Toronto, Ontario, Canada (K.S.P., W.I.L.) and Department of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands (G.J.M.)., Mulder GJ; Leslie Dan Faculty of Pharmacy, University of Toronto, Ontario, Canada (K.S.P., W.I.L.) and Department of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands (G.J.M.). |
| Jazyk: |
angličtina |
| Zdroj: |
Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2024 Jul 16; Vol. 52 (8), pp. 919-931. Date of Electronic Publication: 2024 Jul 16. |
| DOI: |
10.1124/dmd.124.001649 |
| Abstrakt: |
There is overwhelming preference for application of the unphysiologic, well-stirred model (WSM) over the parallel tube model (PTM) and dispersion model (DM) to predict hepatic drug clearance, CL H , despite that liver blood flow is dispersive and closer to the DM in nature. The reasoning is the ease in computation relating the hepatic intrinsic clearance ( CL int ), hepatic blood flow ( Q H ), unbound fraction in blood ( fu b ) and the transmembrane clearances ( CL in and CL ef ) to CL H for the WSM. However, the WSM, being the least efficient liver model, predicts a lower E H that is associated with the in vitro CL int ( V max / K m ), therefore requiring scale-up to predict CL H in vivo. By contrast, the miniPTM, a three-subcompartment tank-in-series model of uniform enzymes, closely mimics the DM and yielded similar patterns for CL int versus E H , substrate concentration [S] , and K L / B , the tissue to outflow blood concentration ratio. We placed these liver models nested within physiologically based pharmacokinetic models to describe the kinetics of the flow-limited, phenolic substrate, harmol, using the WSM (single compartment) and the miniPTM and zonal liver models (ZLMs) of evenly and unevenly distributed glucuronidation and sulfation activities, respectively, to predict CL H For the same, given CL int ( V max and K m ), the WSM again furnished the lowest extraction ratio ( E H,WSM = 0.5) compared with the miniPTM and ZLM (>0.68). Values of E H,WSM were elevated to those for E H, PTM and E H, ZLM when the V max s for sulfation and glucuronidation were raised 5.7- to 1.15-fold. The miniPTM is easily manageable mathematically and should be the new normal for liver/physiologic modeling. SIGNIFICANCE STATEMENT: Selection of the proper liver clearance model impacts strongly on CL H predictions. The authors recommend use of the tank-in-series miniPTM (3 compartments mini-parallel tube model), which displays similar properties as the dispersion model (DM) in relating CL int and [ S ] to CL H as a stand-in for the DM, which best describes the liver microcirculation. The miniPTM is readily modified to accommodate enzyme and transporter zonation.
(Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.) |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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