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Determination of a Human Hepatic Microsomal Scaling Factor for Predicting in Vivo Drug Clearance

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Purpose

To determine a microsomal scaling factor for human liver suitable for prediction of in vivo drug clearance from in vitro data and to explore the role of inter-liver variability in this factor on the reported underprediction from microsomal parameters.

Methods

Cytochrome P450 (henceforth P450) content in whole homogenates and microsomes from 38 donor livers was used to determine a microsomal scaling factor. In a subset (n = 20) of these preparations, individual P450 enzymes were examined by Western blotting and selective probe activities were determined.

Results

The scaling factor from 38 livers averaged 40 mg microsomal protein per gram liver with a coefficient of variation of 31%. Western blotting experiments indicated that there was no P450 enzyme-specific trend in the distribution of individual P450 enzymes in liver microsomes relative to whole homogenate. Predictions based on an average scaling factor resulted in a satisfactory prediction of intrinsic clearance of three benzodiazepines similar to that obtained using individual factors for the same livers.

Conclusion

A value for human liver microsomal scaling of 40 mg microsomal protein per gram liver has been established. The reason for underprediction previously reported for 52 different drug substrates was not the use of an incorrect value for the scaling factor.

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Author information

Author notes

  1. Brian G. Lake

    Present address: Centre for Toxicology, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK

  2. Nancy Hakooz

    Present address: Faculty of Pharmacy, University of Jordan, Amman, 11942, Jordan

  3. Kiyomi Ito

    Present address: School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501, Japan

Authors and Affiliations

  1. School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, M13 9PL, UK

    Nancy Hakooz, Kiyomi Ito, Helen Rawden & J. Brian Houston

  2. Cyprotex, 15 Beech Lane, Macclesfield, Cheshire, SK10 2DR, UK

    Helen Gill & Lynn Lemmers

  3. Division of Medicine, Imperial College, Hammersmith Campus, Ducane Road, London, W12 0NN, UK

    Alan R. Boobis & Robert J. Edwards

  4. Celltec Group plc, 208 Bath Road, Slough, Berkshire, SL1 3WE, UK

    David J. Carlile

  5. BIBRA International Ltd, Woodmansterne Road, Surrey, SM5 4DS, UK

    Brian G. Lake

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  1. Nancy Hakooz
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Corresponding author

Correspondence to J. Brian Houston.

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Hakooz, N., Ito, K., Rawden, H. et al. Determination of a Human Hepatic Microsomal Scaling Factor for Predicting in Vivo Drug Clearance. Pharm Res 23, 533–539 (2006). https://doi.org/10.1007/s11095-006-9531-2

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  • DOI: https://doi.org/10.1007/s11095-006-9531-2

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