Integration of in Vitro Data into Allometric Scaling to Predict Hepatic Metabolic Clearance in Man: Application to 10 Extensively Metabolized Drugs

Lave, T.H.; Dupin, S.; Schmitt, C.; Chou, R.C.; Jaeck, D.; Coassolo, Ph.

doi:10.1021/js960440h

Cited by 184Pharmacogenetics and Drug MetabolismPharmaceutical studies and practicesAnimal testing and alternatives

Integration of in Vitro Data into Allometric Scaling to Predict Hepatic Metabolic Clearance in Man: Application to 10 Extensively Metabolized Drugs

Lave, T.H., Dupin, S., Schmitt, C., Chou, R.C., Jaeck, D., Coassolo, Ph.·1997·Journal of Pharmaceutical Sciences

DOI 10.1021/js960440h

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Abstract

In this study, we investigated rational and reliable methods of using animal data to predict in humans the clearance of drugs which are mainly eliminated through hepatic metabolism. For 10 extensively metabolized compounds, adjusting the in vivo clearance in the different animal species for the relative rates of metabolism in vitro dramatically improved the predictions of human clearance compared to the approach in which clearance is directly extrapolated using body weight. Using hepatocyte data to normalize the in vivo clearances led to lower median deviations between the observed and predicted clearances in man compared to the approach normalizing data with brain weight (30-40% vs 60-80%, respectively). In addition, the approach integrating in vitro data appeared to be superior with respect to the range of deviations: approximately 2-fold underestimation, in the worst case, was observed by using in vitro data, whereas normalizing data by brain weight led to up to 10-fold underestimation of clearance in man. In addition, the integration of in vitro data provides a more rational basis to predict the metabolic clearance in man and may be applicable to compounds undergoing phase I and phase II metabolism as well.

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“Compare with allometric predictions and investigate discrepancies [14,42,100,101].”

Authors: Lave, T. H., Dupin, S., Schmitt, C., Chou, R. C., Jaeck, D., & Coassolo, P.
Affiliations: F. Hoffmann-La Roche AG (CH)
Corresponding author: Lave, T.H.
ORCID: Schmitt, C.
Venue: Journal of Pharmaceutical Sciences
Publisher: American Geophysical Union (AGU)
Published: 1997-05
Volume: 86
Issue: 5
Pages: 584-590
ISSN: 0022-3549 (ISSN-L)
DOI: 10.1021/js960440h
OpenAlex: W1966880707
Cited by: 184
References: 1
Citations by year: 2026: 4 · 2025: 4 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 4 · 2019: 4 · 2018: 4 · 2017: 5 · 2016: 2 · 2015: 5 · 2014: 6 · 2013: 3 · 2012: 9
FWCI: 6.40
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Journal of Pharmaceutical Sciences (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
Keywords: allometric scaling, in vitro-in vivo extrapolation, hepatocyte metabolism, body weight normalization, phase I and phase II metabolism
MeSH terms: Animals, Biological Availability, Humans, Liver, Models, Biological, Pharmacokinetics, Species Specificity

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Integration of in Vitro Data into Allometric Scaling to Predict Hepatic Metabolic Clearance in Man: Application to 10 Extensively Metabolized Drugs

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