Novel In Vitro-In Vivo Extrapolation (IVIVE) Method to Predict Hepatic Organ Clearance in Rat

Umehara, Ken-ichi; Camenisch, Gian

doi:10.1007/s11095-011-0607-2

Cited by 65Pharmacogenetics and Drug MetabolismDrug Transport and Resistance MechanismsDrug-Induced Hepatotoxicity and Protection

Novel In Vitro-In Vivo Extrapolation (IVIVE) Method to Predict Hepatic Organ Clearance in Rat

Umehara, Ken-ichi, Camenisch, Gian·2012·Pharmaceutical Research

DOI 10.1007/s11095-011-0607-2

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Abstract

Purpose Drug elimination in the liver consists of uptake, metabolism, biliary excretion, and sinusoidal efflux from the hepatocytes to the blood. We aimed to establish an accurate prediction method for liver clearance in rats, considering these four elimination processes. In vitro assays were combined to achieve improved predictions. Methods In vitro clearances for uptake, metabolism, biliary excretion and sinusoidal efflux were determined for 13 selected compounds with various physicochemical and pharmacokinetic properties. Suspended hepatocytes, liver microsomes and sandwich-cultured hepatocytes were evaluated as in vitro models. Based on the individual processes, in vivo hepatic clearance was calculated. Subsequently, the predicted clearances were compared with the corresponding in vivo values from literature. Results Using this in vitro-in vivo extrapolation method good linear correlation was observed between predicted and reported clearances. Linear regression analysis revealed much improved prediction for the novel method (r(2) = 0.928) as compared to parameter analysis using hepatocyte uptake only (r(2) = 0.600), microsomal metabolism only (r(2) = 0.687) or overall hepatobiliary excretion in sandwich-cultured hepatocytes (r(2) = 0.321). Conclusions In this new attempt to predict hepatic elimination under consideration of multiple clearance processes, in vivo hepatic clearances of 13 compounds in rats were well predicted using an IVIVE analysis method based on in vitro assays.

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A novel IVIVE method developed to predict hepatic organ clearance via physiology-based modeling reflects additional physiologically relevant information (hepatic uptake, metabolism, biliary excretion, and sinusoidal efflux) compared with the conventional method.
“This new method reflects additional physiologically relevant information (namely hepatic uptake, metabolism, biliary excretion, and sinusoidal efflux) compared with the conventional method.”
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 [73]
The proposed physiology-based IVIVE method was used to predict rat hepatic clearance of 13 compounds with various physicochemical and PK characteristics.
“The proposed method was used to predict rat hepatic clearance of 13 compounds with various physicochemical and PK characteristics.”
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 [73]
In the physiology-based IVIVE studies, the hepatic clearance of valsartan (class 2 compound based on BDDCS) was underestimated with the highest fold-error of 3.95.
“In these studies, the hepatic clearance of valsartan (class 2 compound based on BDDCS) was underestimated with the highest fold-error of 3.95.”
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 [73]

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Authors: Umehara, K.-I., & Camenisch, G.
Affiliations: Novartis (Switzerland) (CH)
ORCID: Camenisch, Gian
Venue: Pharmaceutical Research
Publisher: Springer Science and Business Media LLC
Published: 2011-10-20
Volume: 29
Issue: 2
Pages: 603-617
ISSN: 0724-8741 (ISSN-L)
1573-904X
DOI: 10.1007/s11095-011-0607-2
OpenAlex: W2025284778
Cited by: 65
References: 71
Citations by year: 2026: 1 · 2025: 3 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 6 · 2020: 5 · 2019: 2 · 2018: 3 · 2017: 7 · 2016: 3 · 2015: 9 · 2014: 4 · 2013: 12 · 2012: 6
FWCI: 7.42
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
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: in vitro-in vivo extrapolation, hepatic clearance, hepatocyte uptake, hepatic metabolism, biliary excretion, liver microsomes, sandwich-cultured hepatocytes, rats
MeSH terms: Animals, Biliary Tract, Cells, Cultured, Pharmaceutical Preparations, Liver, Male, Microsomes, Liver, Models, Biological, Rats, Sprague-Dawley, Hepatocytes, Rats

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Novel In Vitro-In Vivo Extrapolation (IVIVE) Method to Predict Hepatic Organ Clearance in Rat

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