Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics and Children's Mercy Research Institute, Children's Mercy Kansas City, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics and Children's Mercy Research Institute, Children's Mercy Kansas City, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri.
Drug Metab Dispos. 2023 Dec;51(12):1578-1582. doi: 10.1124/dmd.123.001417. Epub 2023 Sep 21.
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 ( = 129) and adult ( = 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, = 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).
在基于生理的药代动力学建模和模拟中，为将体外药物生物转化数据转化为体内清除值，需要使用比例因子。目前有多个来源提供每克肝组织中的微粒体蛋白值，可作为估计从微粒体药物生物转化数据估算肝清除率的比例因子。然而，关于肝组织中胞浆蛋白（CPPGL）每克肝组织（liver）的分布数据（across the lifespan）有限，迄今为止，已发表了一些关于儿科数据的稀疏数据。因此，从多个来源（马里兰大学脑和组织库、明尼苏达大学和匹兹堡大学的组织检索服务以及 Sekisui-XenoTech）获得了 160 份来自儿科（n = 129）和成人（n = 31）供体的肝组织样本，对 CPPGL 进行了测定。组织匀浆后进行差速离心以分离胞浆部分。通过 BCA 法测定胞浆蛋白含量。每个年龄组/发育阶段内，CPPGL 的变化范围为两倍至六倍。组织来源和性别对蛋白质含量的变化没有显著影响。回归分析显示，CPPGL 在生命的头二十年变化很小（logCPPGL 每十年增加 0.1 mg/g）。0-18 岁（n = 129）期间观察到的出生至成年早期的 CPPGL 的平均值 ± S.D.为 44.4 ± 17.4 mg/g 或中位数为 41.0 mg/g。意义陈述：每克肝组织中的胞浆蛋白（CPPGL）是基于生理的药代动力学建模和模拟中胞浆酶药物生物转化的比例因子，但儿科数据有限。尽管 CPPGL 在发育阶段内变化范围为两倍至六倍，但 44.4 ± 17.4 mg/g（平均值 ± S.D.）的值代表儿科时期（0-18 岁，n = 129）。
