The Use of Human Hepatocytes to Select Compounds Based on Their Expected Hepatic Extraction Ratios in Humans

Lavé, Th.; Dupin, S.; Schmitt, C.; Valles, B.; Ubeaud, G.; Chou, R. C.; Jaeck, D.; Coassolo, Ph.

doi:10.1023/a:1012036324237

Cited by 106Pharmacogenetics and Drug MetabolismDrug Transport and Resistance MechanismsDrug-Induced Hepatotoxicity and Protection

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The Use of Human Hepatocytes to Select Compounds Based on Their Expected Hepatic Extraction Ratios in Humans

Lavé, Th., Dupin, S., Schmitt, C., Valles, B., Ubeaud, G., Chou, R. C., Jaeck, D., Coassolo, Ph.·1997·Pharmaceutical Research

DOI 10.1023/a:1012036324237

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Abstract

Purpose The present investigation retrospectively evaluates the use of human hepatocytes to classify compounds into low, intermediate or high hepatic extraction ratio in man. Methods A simple approach was used to correlate the in vivo hepatic extraction ratio of a number of compounds in man (literature and in-house data) with the corresponding in vitro clearance which was determined in human hepatocytes. The present approach assumes that, for compounds eliminated mainly through liver metabolism, intrinsic clearance is the major determinant for their in vivo hepatic extraction ratio and subsequently their bioavailability in man. The test compounds were selected to represent a broad range of extraction ratios and a variety of metabolic pathways. Results The present data show that in vitro clearances in human hepatocytes are predictive for the hepatic extraction ratios in vivo in man. Most of the test compounds (n = 19) were successfully classified based upon human hepatocyte data into low, intermediate or high hepatic extraction compounds, i.e. compounds with potential for high, intermediate or low bioavailabilities in humans. Conclusions The present approach, validated so far with 19 test compounds, appears to be a valuable tool to screen for compounds with respect to liver first-pass metabolism at an early phase of drug discovery.

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In Lavé et al.'s method, no protein binding was considered, resulting in overestimation of ERH,pred values of highly bound drugs.
“In this method, no protein binding was considered, resulting in overestimation of ERH,pred values of highly bound drugs.”
From Interpretation of Non-Clinical Data for Prediction of Human Pharmacokinetic Parameters: In Vitro-In Vivo Extrapolation and Allometric Scaling (2019) · cites this paper as [61]
Lavé et al. used human hepatocytes as an in vitro system to predict human ERH, and predicted ERH,pred and CLint,in vitro had a good relationship.
“Another empirical analysis was performed by Lavé et al. [61], who used human hepatocytes as an in vitro system to predict human ERH.”
From Interpretation of Non-Clinical Data for Prediction of Human Pharmacokinetic Parameters: In Vitro-In Vivo Extrapolation and Allometric Scaling (2019) · cites this paper as [61]

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“7 [61] ERH,pred = SF·CLint,in vitro QH+(SF·CLint,in vitro) (41)”
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Authors: Lavé, T., Dupin, S., Schmitt, C., Valles, B., Ubeaud, G., Chou, R. C., Jaeck, D., & Coassolo, P.
ORCID: Schmitt, C.
Venue: Pharmaceutical Research
Publisher: Springer Science and Business Media LLC
Published: 1997-02
Volume: 14
Issue: 2
Pages: 152-155
ISSN: 0724-8741 (ISSN-L)
1573-904X
DOI: 10.1023/a:1012036324237
OpenAlex: W1264367399
Cited by: 106
References: 22
Citations by year: 2026: 1 · 2024: 1 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 9 · 2015: 7 · 2014: 2 · 2013: 5 · 2012: 2
FWCI: 5.29
Type: journal article
Language: en
Open access: closed
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Pharmaceutical Research (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords: human hepatocytes, hepatic extraction ratio, intrinsic clearance, in vitro-in vivo correlation, bioavailability prediction, first-pass metabolism, drug discovery screening, hepatic metabolism, compound classification
MeSH terms: Adult, Aged, Biological Availability, Cells, Cultured, Drug Evaluation, Preclinical, Pharmaceutical Preparations, Humans, Liver, Metabolic Clearance Rate, Middle Aged, Pharmacokinetics

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The Use of Human Hepatocytes to Select Compounds Based on Their Expected Hepatic Extraction Ratios in Humans

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