The DOI matches its Crossref record; 22 of the 22 references it cites were found in a registry or an index.
The Use of Human Hepatocytes to Select Compounds Based on Their Expected Hepatic Extraction Ratios in Humans
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 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]
In the citing paper
“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]
Citations
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Holford, N. H. G. (1986) · Clinical Pharmacokinetics · doi:10.2165/00003088-198611060-00005 · Cited by 362
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Clinical Importance of Hepatic Cytochrome P450 in Drug Metabolism
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Pharmacokinetics and plasma binding of diazepam in man, dog, rabbit, guinea pig and rat.
Klotz, U. E., Antonin, K. H., & Bieck, P. R. (1976) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)30657-9 · Cited by 213
Interspecies Comparison of In Vivo Caffeine Pharmacokinetics in Man, Monkey, Rabbit, Rat and Mouse
Bonati, M. R., Latini, R., Tognoni, G., Young, J. F., & Garattini, S. K. (1984) · Drug Metabolism Reviews · doi:10.3109/03602538409029964 · Cited by 171
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Physiological Models for Drug Metabolism and Excretion
Peters, S. A. (2012) · doi:10.1002/9781118140291.ch6
Physiologically-Based Models to Predict Human Pharmacokinetic Parameters
Lavee, T., Parrott, N. J., & Jones, H. M. (2007) · Elsevier eBooks · doi:10.1016/b0-08-045044-x/00153-x
tools for the prediction of metabolic clearance
McGinnity, D. F., Soars, M. G., Urbanowicz, R. A., & Riley, R. J. (2004)
The Role Of Drug Metabolism And Pharmacokinetics In Drug Discovery
Tarbit, M. (2004) · CRC Press eBooks · doi:10.1201/9780203642535.ch19
Integrated Lead Optimization: Translational Models as We Advance Toward the Clinic
Liederer, B. M., Liu, X., Wong, S. G. W., & Mudra, D. R. (2017) · AAPS advances in the pharmaceutical sciences series · doi:10.1007/978-3-319-50042-3_6
Daripelli, S., Raje, A. A., Kandikere, V. N., & Kumar, P. R. A. V. (2026) · Xenobiotica · doi:10.1080/00498254.2026.2637031
Metadata
- Authors
- Lavé, T., Dupin, S., Schmitt, C., Valles, B., Ubeaud, G., Chou, R. C., Jaeck, D., & Coassolo, P.
- ORCID
- Schmitt, C.
- Venue
- Pharmaceutical Research
- Published
- 1997-02
- Volume
- 14
- Issue
- 2
- Pages
- 152-155
- ISSN
- 0724-8741 (ISSN-L)
- 1573-904X
- 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
- 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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