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Research ArticleArticle

Ontogeny of Scaling Factors for Pediatric Physiology-Based Pharmacokinetic Modeling and Simulation: Microsomal Protein Per Gram of Liver

J. Steven Leeder, Jean C. Dinh, Andrea Gaedigk, Vincent S. Staggs, Bhagwat Prasad and Robin E. Pearce
Drug Metabolism and Disposition January 2022, 50 (1) 24-32; DOI: https://doi.org/10.1124/dmd.121.000623
J. Steven Leeder
Certara, Princeton, NJ (J.C.D.); Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics and Children’s Mercy Research Institute, Children's Mercy Kansas City, Kansas City, Missouri (J.S.L., J.C.D., A.G., V.S.S., R.E.P.); Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (B.P.)
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Jean C. Dinh
Certara, Princeton, NJ (J.C.D.); Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics and Children’s Mercy Research Institute, Children's Mercy Kansas City, Kansas City, Missouri (J.S.L., J.C.D., A.G., V.S.S., R.E.P.); Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (B.P.)
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Andrea Gaedigk
Certara, Princeton, NJ (J.C.D.); Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics and Children’s Mercy Research Institute, Children's Mercy Kansas City, Kansas City, Missouri (J.S.L., J.C.D., A.G., V.S.S., R.E.P.); Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (B.P.)
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Vincent S. Staggs
Certara, Princeton, NJ (J.C.D.); Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics and Children’s Mercy Research Institute, Children's Mercy Kansas City, Kansas City, Missouri (J.S.L., J.C.D., A.G., V.S.S., R.E.P.); Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (B.P.)
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Bhagwat Prasad
Certara, Princeton, NJ (J.C.D.); Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics and Children’s Mercy Research Institute, Children's Mercy Kansas City, Kansas City, Missouri (J.S.L., J.C.D., A.G., V.S.S., R.E.P.); Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (B.P.)
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Robin E. Pearce
Certara, Princeton, NJ (J.C.D.); Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics and Children’s Mercy Research Institute, Children's Mercy Kansas City, Kansas City, Missouri (J.S.L., J.C.D., A.G., V.S.S., R.E.P.); Department of Pharmaceutical Sciences, Washington State University, Spokane, Washington (B.P.)
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Abstract

Microsomal protein per gram of liver (MPPGL) is an important scaling factor for bottom-up physiology-based pharmacokinetic modeling and simulation, but data in pediatrics are limited. Therefore, MPPGL was determined in 160 liver samples from pediatric (n = 129) and adult (n = 31) donors obtained from four sources: the University of Maryland Brain and Tissue Bank (UMBTB), tissue retrieval services at the University of Minnesota and University of Pittsburgh, and Sekisui-Xenotech. Tissues were homogenized and subjected to differential centrifugation to prepare microsomes, and cytochrome c reductase activities in tissue homogenates and microsomes were used to estimate cytochrome P450 reductase (POR) activity as a marker of microsomal recovery; microsomal POR content was also assessed by quantitative proteomics. MPPGL values varied 5- to 10-fold within various age groups/developmental stages, and tissue source was identified as a contributing factor. Using a “trimmed” dataset comprised of samples ranging from 3 to 18 years of age common to the four sources, POR protein abundance and activity in microsomes and POR activity in homogenates was lower in UMBTB samples (autopsy) compared with other sources (perfused/flash-frozen). Regression analyses revealed that the UMBTB samples were driving an apparent age effect as no effect of age on log-transformed MPPGL values was observed when the UMBTB samples were excluded. We conclude that a mean±SD MPPGL value of 30.4±1.7 mg/g is representative between one month postnatal age and early adulthood. Potential source effects should be considered for studies involving tissue samples from multiple sources with different procurement and processing procedures.

SIGNIFICANCE STATEMENT Microsomal protein per gram of liver (MPPGL) is an important scaling factor for bottom up PBPK modeling and simulation, but data in pediatrics are limited. Although MPPGL varies 5- to 10-fold at a given developmental stage, a value of 30.4 ± 1.7 mg/g (mean ± SD) is representative between one month postnatal age and early adulthood. However, when tissue samples are obtained from multiple sources, different procurement and processing procedures may influence the results and should be taken into consideration.

Footnotes

    • Received July 22, 2021.
    • Accepted October 20, 2021.
  • ↵1 Current affiliation: Certara, Princeton, New Jersey.

  • Tissues used in this study were acquired from publicly supported tissue repositories, including the National Institutes of Health (NIH)-funded University of Maryland Brain and Tissue Bank for Developmental Disorders (funded by NIH contract HHSN275200900011C, Ref. No. #N01-HD-9-0011) and The Liver Tissue Cell Distribution System (funded by NIH contract #N01-DK-7-0004/HHSN267200700004C). The work was supported by grants P50 HD090258 (J.S.L.) and R01-HD081299 (B.P.) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • https://dx.doi.org/10.1124/dmd.121.000623.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 50 (1)
Drug Metabolism and Disposition
Vol. 50, Issue 1
1 Jan 2022
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Research ArticleArticle

Ontogeny of MPPGL in Pediatric Liver

J. Steven Leeder, Jean C. Dinh, Andrea Gaedigk, Vincent S. Staggs, Bhagwat Prasad and Robin E. Pearce
Drug Metabolism and Disposition January 1, 2022, 50 (1) 24-32; DOI: https://doi.org/10.1124/dmd.121.000623

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Research ArticleArticle

Ontogeny of MPPGL in Pediatric Liver

J. Steven Leeder, Jean C. Dinh, Andrea Gaedigk, Vincent S. Staggs, Bhagwat Prasad and Robin E. Pearce
Drug Metabolism and Disposition January 1, 2022, 50 (1) 24-32; DOI: https://doi.org/10.1124/dmd.121.000623
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