Corticosteroid Pharmacokinetics and Pharmacodynamics

皮质类固醇药代动力学和药效学

• 批准号: 9298670
• 负责人: WILLIAM J. JUSKO
• 金额: $ 68.85万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9298670
• 关键词: Acute; Address; Adrenal Cortex Hormones; Advanced Development; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Biochemical Markers; Biological; Biological Markers; Biological Process; Biology; Bioperiodicity; Blood; Bone Density; Chronic; Circadian Rhythms; Collagen-Induced Arthritis; Complement; Complex; Computer Simulation; Controlled Study; Cytokine Gene; Data Files; Development; Dexamethasone; Diabetes Mellitus; Disease; Disease model; Dose; Drug Kinetics; Estrogens; Estrous Cycle; Estrus; Fatty Acids; Fatty acid glycerol esters; Female; Functional disorder; Gene Expression; Gene Proteins; Genes; Genomics; Glucocorticoid Receptor; Glucose; Goals; Harvest; Homeostasis; Immunosuppression; Incidence; Inflammation; Inflammatory; Infusion procedures; Insulin; Interleukin-1 beta; Interleukin-6; Knowledge; Leptin; Liver; Lung; Lymphocyte; Measurement; Measures; Metabolic; Methodology; Methylprednisolone; Modeling; Muscle; Nonesterified Fatty Acids; Organ; Osteocalcin; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Pharmacology; Pharmacotherapy; Physiological; Physiological Processes; Plasma; Process; Progesterone; Proteomics; Rattus; Recovery; Research; Rheumatoid Arthritis; Sex Characteristics; Steroids; Study models; System; Systems Biology; TNF gene; Time; Tissues; Uterus; adiponectin; base; biomarker panel; bone; bone turnover; diabetogenic; dynamic system; early onset; experimental study; human female; immune function; improved; in vivo; innovation; insight; interest; mRNA Expression; male; mathematical model; protein biomarkers; public health relevance; receptor; response; sex; tissue biomarkers; treatment response

 DESCRIPTION (provided by applicant): This project seeks to provide increased understanding of pharmacokinetics and mechanisms of corticosteroid (CS) effects on genomic and physiologic processes associated with endocrinologic, metabolic, and pharmacologic responses from local to systemic levels for CS dosed acutely and chronically. Our continued research will expand our mechanistic assessments to address gaps in knowledge about important sex differences. We also seek to continue development of pharmacokinetic, pharmacodynamic, pharmacogenomic (PK/PD/PG) and Disease (DIS) models that reveal the `rules of biology' at various levels of biological organization (systems biology) and allow improved quantitation and prediction of in vivo drug effects. Our experimental paradigm has often been large carefully-controlled studies in groups of animals subjected to defined conditions or drug treatments ("giant rat" studies). Blood and major organs of male rats were harvested over time frames reflecting either endogenous biorhythms and/or the onset and recovery of changes produced by single-doses or prolonged disturbances of homeostasis produced by chronic exposures of CS. We will expand computations and modeling for the interaction of a short rhythm (circadian) within a longer biorhythm (estrous cycle), further examine sex differences in steroid actions, and evolve more physiologically-relevant small to extensive systems pharmacologic models. Specific Aim 1 will elucidate sex differences in circadian rhythms by extending our core experimental paradigm to provide carefully-enacted baseline (circadian/estrous cycle) profiles of diverse genes and biomarkers in normal cycling female rats as a function of estrous stage. Specific Aim 2 will assess the PK/PD of single doses of a prototypic CS, methylprednisolone, in cycling intact female rats as a function of cycle stage to examine sex determinants of the diabetogenic glucose/insulin/adiponectin/fatty acid system and bone turnover systems. Specific Aim 3 will extend our previous use of the collagen-induced arthritis model in male rats to females. We will evolve basic to complex mathematical models for inflammatory and bone dynamic processes to account for sex differences, combining these new measurements with our extensive data files from normal and arthritic male rats. Specific Aim 4 will employ and evolve "top-down" computational approaches to assess circadian rhythms and global responsiveness to CS of genes, proteins, and biomarkers in blood and tissues to reveal potential indirect regulatory mechanisms in male versus female animals. These holistic studies and mathematical modeling innovations will provide improved multi-scale understanding of critical biological functions where sex differences are highly relevant and will have wide applications in quantitative pharmacology.

 描述（由申请人提供）：本项目旨在加深对皮质类固醇（CS）急性和慢性给药的局部至全身水平的内分泌、代谢和药理学反应相关基因组和生理过程的药代动力学和机制的理解。我们继续的研究将扩大我们的机械评估，以解决有关重要性别差异的知识差距。我们还寻求继续开发药代动力学，药效学，药物基因组学（PK/PD/PG）和疾病（DIS）模型，这些模型揭示了生物组织（系统生物学）各个层次的“生物学规则”，并允许改进体内药物作用的定量和预测。我们的实验范式通常是在动物群体中进行的大型仔细对照研究，这些动物群体受到规定的条件或药物治疗（"巨鼠"研究）。在反映内源性生物节律和/或单次给药或长期暴露于CS产生的稳态紊乱所产生的变化的发生和恢复的时间范围内采集雄性大鼠的血液和主要器官。我们将扩大计算和建模的一个较长的生物节律（发情周期）内的短节奏（昼夜节律）的相互作用，进一步研究类固醇作用的性别差异，并发展更多的生理相关的小到广泛的系统药理学模型。具体目标1将阐明昼夜节律的性别差异，通过扩展我们的核心实验范式，提供精心制定的基线（昼夜节律/发情周期）配置文件的不同基因和生物标志物在正常的周期性雌性大鼠发情阶段的功能。具体目标2将评估原型CS（甲基强的松龙）单次给药在周期完整雌性大鼠中的PK/PD（作为周期阶段的函数），以检查致糖尿病葡萄糖/胰岛素/脂联素/脂肪酸系统和骨转换系统的性别决定因素。Specific Aim 3将我们之前在雄性大鼠中使用的胶原蛋白诱导的关节炎模型扩展到雌性。我们将从基本到复杂的炎症和骨动力学过程的数学模型来解释性别差异，将这些新的测量结果与我们从正常和关节炎雄性大鼠获得的大量数据文件相结合。具体目标4将采用和发展“自上而下”的计算方法来评估昼夜节律和对血液和组织中基因，蛋白质和生物标志物的CS的全球反应性，以揭示雄性与雌性动物的潜在间接调节机制。这些整体研究和数学建模创新将提供更好的多尺度理解关键的生物功能，其中性别差异是高度相关的，并将在定量药理学中有广泛的应用。