{"title":"肝清除模型问世五十年后,我们该何去何从?PBPK 模型的改进和影响","authors":"K. Sandy Pang, Weijia Ivy Lu, Gerard J. Mulder","doi":"10.1124/dmd.124.001649","DOIUrl":null,"url":null,"abstract":"There is overwhelming preference for application of the unphysiologic, well-stirred model (WSM) over the parallel tube (PTM) and dispersion (DM) models to predict hepatic drug clearance, CLH, 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<sub>int</sub>), hepatic blood flow (Q<sub>H</sub>), unbound fraction in blood (fu<sub>b</sub>) and the transmembrane clearances (CL<sub>in</sub> and CL<sub>ef</sub>) to CL<sub>H</sub> for the WSM. However, the WSM, being the least efficient liver model, predicts a lower E<sub>H</sub> that is associated with the in vitro CL<sub>int</sub> (V<sub>max</sub>/K<sub>m</sub>), therefore requiring scale-up to predict CL<sub>H</sub> in vivo. By contrast, the miniPTM, a 3-subcompartment tanks-in-series model of uniform enzymes, closely mimics the DM and yielded similar patterns for CL<sub>int</sub> vs. E<sub>H</sub>, substrate concentration [S], and K<sub>L/B</sub>, the tissue to outflow blood concentration ratio. We placed these liver models nested within PBPK models to describe the kinetics of the flow-limited, phenolic substrate, harmol, using the WSM (single compartment) and the miniPTM and ZLM (zonal liver) models of evenly- and unevenly-distributed glucuronidation and sulfation activities, respectively, to predicted CL<sub>H</sub>. For the same, given CL<sub>int</sub> (V<sub>max</sub> and K<sub>m</sub>), the WSM again furnished the lowest extraction ratio (E<sub>H,WSM</sub> = 0.5) compared to the miniPTM and ZLM (>0.68). Values of E<sub>H,WSM</sub> were elevated to those for E<sub>H,PTM</sub> and E<sub>H,ZLM</sub> when the V<sub>maxs</sub> 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/physiological modeling.","PeriodicalId":11309,"journal":{"name":"Drug Metabolism and Disposition","volume":null,"pages":null},"PeriodicalIF":4.4000,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"After fifty years of hepatic clearance models, where should we go from here? Improvements and implications for PBPK modeling\",\"authors\":\"K. Sandy Pang, Weijia Ivy Lu, Gerard J. Mulder\",\"doi\":\"10.1124/dmd.124.001649\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"There is overwhelming preference for application of the unphysiologic, well-stirred model (WSM) over the parallel tube (PTM) and dispersion (DM) models to predict hepatic drug clearance, CLH, 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<sub>int</sub>), hepatic blood flow (Q<sub>H</sub>), unbound fraction in blood (fu<sub>b</sub>) and the transmembrane clearances (CL<sub>in</sub> and CL<sub>ef</sub>) to CL<sub>H</sub> for the WSM. However, the WSM, being the least efficient liver model, predicts a lower E<sub>H</sub> that is associated with the in vitro CL<sub>int</sub> (V<sub>max</sub>/K<sub>m</sub>), therefore requiring scale-up to predict CL<sub>H</sub> in vivo. By contrast, the miniPTM, a 3-subcompartment tanks-in-series model of uniform enzymes, closely mimics the DM and yielded similar patterns for CL<sub>int</sub> vs. E<sub>H</sub>, substrate concentration [S], and K<sub>L/B</sub>, the tissue to outflow blood concentration ratio. We placed these liver models nested within PBPK models to describe the kinetics of the flow-limited, phenolic substrate, harmol, using the WSM (single compartment) and the miniPTM and ZLM (zonal liver) models of evenly- and unevenly-distributed glucuronidation and sulfation activities, respectively, to predicted CL<sub>H</sub>. For the same, given CL<sub>int</sub> (V<sub>max</sub> and K<sub>m</sub>), the WSM again furnished the lowest extraction ratio (E<sub>H,WSM</sub> = 0.5) compared to the miniPTM and ZLM (>0.68). Values of E<sub>H,WSM</sub> were elevated to those for E<sub>H,PTM</sub> and E<sub>H,ZLM</sub> when the V<sub>maxs</sub> 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/physiological modeling.\",\"PeriodicalId\":11309,\"journal\":{\"name\":\"Drug Metabolism and Disposition\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.4000,\"publicationDate\":\"2024-05-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Drug Metabolism and Disposition\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1124/dmd.124.001649\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Metabolism and Disposition","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1124/dmd.124.001649","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
After fifty years of hepatic clearance models, where should we go from here? Improvements and implications for PBPK modeling
There is overwhelming preference for application of the unphysiologic, well-stirred model (WSM) over the parallel tube (PTM) and dispersion (DM) models to predict hepatic drug clearance, CLH, 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 (CLint), hepatic blood flow (QH), unbound fraction in blood (fub) and the transmembrane clearances (CLin and CLef) to CLH for the WSM. However, the WSM, being the least efficient liver model, predicts a lower EH that is associated with the in vitro CLint (Vmax/Km), therefore requiring scale-up to predict CLH in vivo. By contrast, the miniPTM, a 3-subcompartment tanks-in-series model of uniform enzymes, closely mimics the DM and yielded similar patterns for CLint vs. EH, substrate concentration [S], and KL/B, the tissue to outflow blood concentration ratio. We placed these liver models nested within PBPK models to describe the kinetics of the flow-limited, phenolic substrate, harmol, using the WSM (single compartment) and the miniPTM and ZLM (zonal liver) models of evenly- and unevenly-distributed glucuronidation and sulfation activities, respectively, to predicted CLH. For the same, given CLint (Vmax and Km), the WSM again furnished the lowest extraction ratio (EH,WSM = 0.5) compared to the miniPTM and ZLM (>0.68). Values of EH,WSM were elevated to those for EH,PTM and EH,ZLM when the Vmaxs 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/physiological modeling.
期刊介绍:
An important reference for all pharmacology and toxicology departments, DMD is also a valuable resource for medicinal chemists involved in drug design and biochemists with an interest in drug metabolism, expression of drug metabolizing enzymes, and regulation of drug metabolizing enzyme gene expression. Articles provide experimental results from in vitro and in vivo systems that bring you significant and original information on metabolism and disposition of endogenous and exogenous compounds, including pharmacologic agents and environmental chemicals.