期刊
BIOCHEMICAL PHARMACOLOGY
卷 169, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2019.07.025
关键词
Hepatic drug clearance models; Hepatic extraction ratio and availability; Well-stirred, parallel tube and dispersion, models; Heterogeneity in flow, enzymes, transporters
资金
- Center for Collaborative Drug Research (CCDR), Department of Pharmacology, University of Toronto
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- National Research Foundation of Korea [2017R1A6A3A03009065]
- National Research Foundation of Korea [2017R1A6A3A03009065] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
The liver is the most important drug metabolizing organ, endowed with a plethora of metabolizing enzymes and transporters to facilitate drug entry and removal via metabolism and/or biliary excretion. For this reason, much focus surrounds the development of clearance concepts, which are based on normalizing the rate of removal to the input or arterial concentration. By so doing, some authors have recently claimed that it implies one specific model of hepatic elimination, namely, the widely used well-stirred or venous equilibration model (WSM). This commentary challenges this claim and aims to provide a comprehensive discussion of not only the WSM but other currently applied hepatic clearance models - the parallel tube model (PTM), the dispersion model (DM), the zonal liver model (ZLM), and the heterogeneous capillary transit time model of Goresky and co-workers (GM). The WSM, PTM, and DM differ in the patterns of internal blood flow, assuming bulk, plug, and dispersive flows, respectively, which render different degrees of mixing within the liver that are characterized by the magnitudes of the dispersion number (DN), resulting in different implications concerning the (unbound) substrate concentration in liver (CuH). Early models assumed perfusion rate-limited distribution, which have since been modified to include membrane-limited transport. The recent developments associated with the misconceptions and the sensitivity of the models are hereby addressed. Since the WSM has been and will likely remain widely used, the pros and cons of this model relative to physiological reality are further discussed.
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