Scaling Factors for the Extrapolation of In Vivo Metabolic Drug Clearance From In Vitro Data: Reaching a Consensus on Values of Human Micro-somal Protein and Hepatocellularity Per Gram of Liver

Barter, Zoe; Bayliss, Martin; Beaune, Philip; Boobis, Alan; Carlile, David; Edwards, Robert; Brian Houston, J.; Lake, Brian; Lipscomb, John; Pelkonen, Olavi; Tucke, Geoffrey; Rostami-Hodjegan, Amin

doi:10.2174/138920007779315053

Cited by 459Pharmacogenetics and Drug MetabolismPharmaceutical studies and practicesDrug-Induced Hepatotoxicity and Protection

Scaling Factors for the Extrapolation of In Vivo Metabolic Drug Clearance From In Vitro Data: Reaching a Consensus on Values of Human Micro-somal Protein and Hepatocellularity Per Gram of Liver

Barter, Zoe, Bayliss, Martin, Beaune, Philip, Boobis, Alan, Carlile, David, Edwards, Robert, Brian Houston, J., Lake, Brian +4 more·2007·Current Drug Metabolism

DOI 10.2174/138920007779315053

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Abstract

Reported predictions of human in vivo hepatic clearance from in vitro data have used a variety of values for the scaling factors human microsomal protein (MPPGL) and hepatocellularity (HPGL) per gram of liver, generally with no consideration of the extent of their inter-individual variability. We have collated and analysed data from a number of sources, to provide weighted meangeo values of human MPPGL and HPGL of 32 mg g-1 (95% Confidence Interval (CI); 29-34 mg.g-1) and 99x10(6) cells.g-1 (95% CI; 74-131 mg.g-1), respectively. Although inter-individual variability in values of MPPGL and HPGL was statistically significant, gender, smoking or alcohol consumption could not be detected as significant covariates by multiple linear regression. However, there was a weak but statistically significant inverse relationship between age and both MPPGL and HPGL. These findings indicate the importance of considering differences between study populations when forecasting in vivo pharmacokinetic behaviour. Typical clinical pharmacology studies, particularly in early drug development, use young, fit, healthy male subjects of around 30 years of age. In contrast, the average age of patients for many diseases is about 60 years of age. The relationship between age and MPPGL observed in this study estimates values of 40 mg.g-1 for a 30 year old individual and 31 mg.g-1 for a 60 year old individual. Investigators may wish to consider the reported covariates in the selection of scaling factors appropriate for the population in which estimates of clearance are being predicted. Further studies are required to clarify the influence of age (especially in paediatric subjects), donor source and ethnicity on values of MPPGL and HPGL. In the meantime, we recommend that the estimates (and their variances) from the current meta-analysis be used when predicting in vivo kinetic parameters from in vitro data.

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Since pharmacogenetic data of laboratory animal models are less than those of humans, the variation in MPPGL of humans may be greater than that of rats.
“Since the pharmacogenetic data of laboratory animal models are less than those of humans because of their genetics and environment, the variation in MPPGL of humans may be greater than that of rats [78].”
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 [78]
Barter et al. reported an inverse correlation between age and MPPGL.
“In their studies, the authors reported an inverse correlation between age and MPPGL.”
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 [78]
MPPGL values range from 40 mg/g and 31 mg/g for those in their 30s and 60s, respectively.
“The MPPGL values range from 40 mg/g and 31 mg/g for those in their 30s and 60s, respectively.”
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 [78]

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MethodInfluential
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Scaling factors for the in vitro-in vivo extrapolation (IV-IVE) of renal drug and xenobiotic glucuronidation clearance.
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Authors: Barter, Z., Bayliss, M., Beaune, P., Boobis, A., Carlile, D., Edwards, R., Brian Houston, J., Lake, B., Lipscomb, J., Pelkonen, O., Tucke, G., & Rostami-Hodjegan, A.
Affiliations: Royal Hallamshire Hospital (GB)
ORCID: Boobis, Alan
Carlile, David
Edwards, Robert
Lake, Brian
Lipscomb, John
Pelkonen, Olavi
Venue: Current Drug Metabolism
Publisher: Bentham Science Publishers Ltd.
Published: 2007-01-01
Volume: 8
Issue: 1
Pages: 33-45
ISSN: 1389-2002 (ISSN-L)
DOI: 10.2174/138920007779315053
OpenAlex: W2161213051
Cited by: 459
References: 0
Citations by year: 2026: 16 · 2025: 21 · 2024: 19 · 2023: 16 · 2022: 27 · 2021: 29 · 2020: 26 · 2019: 25 · 2018: 23 · 2017: 18 · 2016: 21 · 2015: 23 · 2014: 22 · 2013: 31 · 2012: 44
FWCI: 14.67
Type: journal article
Language: en
Open access: closed
Locations: Current Drug Metabolism (publishedVersion)
PubMed (publishedVersion)
Research Explorer (The University of Manchester) (submittedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords: scale factor, in vitro-in vivo extrapolation, hepatic clearance, interindividual variability, age effects, population pharmacokinetics, drug metabolism
MeSH terms: Animals, Drug Evaluation, Preclinical, Pharmaceutical Preparations, Humans, Liver, Microsomes, Liver, Proteins, Hepatocytes

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Scaling Factors for the Extrapolation of In Vivo Metabolic Drug Clearance From In Vitro Data: Reaching a Consensus on Values of Human Micro-somal Protein and Hepatocellularity Per Gram of Liver

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