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OtherShort Communication

Covariation of Human Microsomal Protein Per Gram of Liver with Age: Absence of Influence of Operator and Sample Storage May Justify Interlaboratory Data Pooling

Z. E. Barter, J. E. Chowdry, J. R. Harlow, J. E. Snawder, J. C. Lipscomb and A. Rostami-Hodjegan
Drug Metabolism and Disposition December 2008, 36 (12) 2405-2409; DOI: https://doi.org/10.1124/dmd.108.021311
Z. E. Barter
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J. E. Chowdry
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J. R. Harlow
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J. E. Snawder
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J. C. Lipscomb
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A. Rostami-Hodjegan
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Abstract

Scaling of metabolic clearance values from liver microsomal data or recombinantly expressed cytochrome P450 enzymes to predict human hepatic clearance requires knowledge of the amount of microsomal protein per gram of liver (MPPGL). Identification of physiological covariates of MPPGL requires analysis of values from large diverse populations, which necessitates pooling of data from numerous sources. To ensure compatibility between results obtained within and between studies, the impact of interoperator differences and sample storage on values of MPPGL was investigated. With use of triplicate samples from one liver (HL86), no statistically significant difference was detected between values of MPPGL prepared from samples stored at -80°C (23.5 ± 1.2 mg g-1) and those determined using fresh tissue (21.9 ± 0.3 mg g-1). Although there was a significant difference in the yield of microsomal protein obtained from another liver sample (HL43) by three different operators (17 ± 1, 19 ± 2, and 24 ± 1 mg g-1; p = 0.004, analysis of variance), no difference was observed in the estimated MPPGL after application of appropriate correction factors for each operator (28 ± 1, 30 ± 5, and 31 ± 4 mg g-1). The result provided justification for pooling reported values of MPPGL for use in covariate analysis. Investigation of the relationship between age and MPPGL provided preliminary evidence that MPPGL values increase from birth to a maximum of 40 mg g-1 [95% confidence interval for the geometric mean (95% CI meangeo): 37–43 mg g-1 at approximately 28 years followed by a gradual decrease in older age (mean of 29 mg g-1 at 65 years; 95% CI meangeo: 27–32 mg g-1). Accordingly, appropriate age-adjusted scaling factors should be used in extrapolating in vitro clearance values to clinical studies.

Footnotes

  • Z.E.B. was supported by Simcyp Ltd., (Sheffield, UK) and European Union Framework 6 (BIOSIM).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.021311.

  • ABBREVIATIONS: IVIVE, in vitro-in vivo extrapolation; MSP, microsomal protein; MPPGL, microsomal protein per gram of liver; P450, cytochrome P450; ANOVA, analysis of variance; AIC, Akaike's information criterion; 95% CI meangeo, 95% confidence interval for the geometric mean; 95% CI obs, 95% confidence interval for the likelihood of observations.

    • Received March 4, 2008.
    • Accepted September 4, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (12)
Drug Metabolism and Disposition
Vol. 36, Issue 12
1 Dec 2008
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OtherShort Communication

Covariation of Human Microsomal Protein Per Gram of Liver with Age: Absence of Influence of Operator and Sample Storage May Justify Interlaboratory Data Pooling

Z. E. Barter, J. E. Chowdry, J. R. Harlow, J. E. Snawder, J. C. Lipscomb and A. Rostami-Hodjegan
Drug Metabolism and Disposition December 1, 2008, 36 (12) 2405-2409; DOI: https://doi.org/10.1124/dmd.108.021311

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OtherShort Communication

Covariation of Human Microsomal Protein Per Gram of Liver with Age: Absence of Influence of Operator and Sample Storage May Justify Interlaboratory Data Pooling

Z. E. Barter, J. E. Chowdry, J. R. Harlow, J. E. Snawder, J. C. Lipscomb and A. Rostami-Hodjegan
Drug Metabolism and Disposition December 1, 2008, 36 (12) 2405-2409; DOI: https://doi.org/10.1124/dmd.108.021311
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