Ontogeny of Scaling Factors for Pediatric Physiologically Based Pharmacokinetic Modeling and Simulation: Cytosolic Protein Per Gram of Liver.
Scaling factors are necessary for translating in vitro drug biotransformation data to in vivo clearance values in physiologically-based pharmacokinetic modeling and simulation. Values for microsomal protein per gram of liver are available from several sources for use as a scaling factor to estimate hepatic clearance from microsomal drug biotransformation data. However, data regarding the distribution of cytosolic protein per gram of liver (CPPGL) values across the lifespan are limited, and sparse pediatric data have been published to date. Thus, CPPGL was determined in 160 liver samples from pediatric (n = 129) and adult (n = 31) donors obtained from multiple sources: the University of Maryland Brain and Tissue Bank, tissue retrieval services at the University of Minnesota and University of Pittsburgh, and Sekisui-XenoTech. Tissues were homogenized and subjected to differential centrifugation to isolate cytosolic fractions. Cytosolic protein content was determined by BCA assay. CPPGL varied from two- to sixfold within each age group/developmental stage. Tissue source and sex did not contribute substantially to variability in protein content. Regression analyses revealed minimal change in CPPGL over the first two decades of life (logCPPGL increases 0.1 mg/g per decade). A mean ± S.D. CPPGL value of 44.4 ± 17.4 mg/g or median 41.0 mg/g is representative of values observed between birth and early adulthood (0-18 years, n = 129). SIGNIFICANCE STATEMENT: Cytosolic protein per gram of liver (CPPGL) is a scaling factor required for physiologically based pharmacokinetic modeling and simulation of drug biotransformation by cytosolic enzymes, but pediatric data are limited. Although CPPGL varies from two- to sixfold within developmental stages, a value of 44.4 ± 17.4 mg/g (mean ± S.D.) is representative of the pediatric period (0-18 years, n = 129).
Drug metabolism and disposition: the biological fate of chemicals
Adult; Humans; Child; Microsomes, Liver; Liver; Proteins; Metabolic Clearance Rate; Cytosol; Models, Biological
Liver Microsomes; Liver; Proteins; Metabolic Clearance Rate; Cytosol; Biological Models
Stancil SL, Pearce RE, Staggs VS, Leeder JS. Ontogeny of Scaling Factors for Pediatric Physiologically Based Pharmacokinetic Modeling and Simulation: Cytosolic Protein Per Gram of Liver. Drug Metab Dispos. 2023;51(12):1578-1582. doi:10.1124/dmd.123.001417