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Corticosteroid (CS) pharmacogenomics was studied using gene microarrays in rat liver. Methylprednisolone (MPL) was administered intravenously at 50 mg/kg. Rats were sacrificed and liver excised at 17 time points over 72 h. RNAs from individual livers were used to query Affymetrix GeneChips that contain sequences for 8000 genes. Cluster analysis revealed six(More)
This study describes a pharmacokinetic (PK) model to account for serum recombinant human erythropoietin (rHuEpo) concentrations in healthy volunteers following intravenous (IV) and subcutaneous (SC) dosing; it also characterizes the pharmacodynamics (PD) of SC rHuEpo effects on reticulocytes, red blood cells (RBC), and hemoglobin (Hb) in blood. Data were(More)
Four basic models for characterizing indirect pharmacodynamic responses after drug administration have been developed and compared. The models are based on drug effects (inhibition or stimulation) on the factors controlling either the input or the dissipation of drug response. Pharmacokinetic parameters of methylprednisolone were used to generate plasma(More)
Drugs that bind with high affinity and to a significant extent (relative to dose) to a pharmacologic target such as an enzyme, receptor, or transporter may exhibit nonlinear pharmacokinetic (PK) behavior. Processes such as receptor-mediated endocytosis may result in drug elimination. A general PK model for characterizing such behavior is described and(More)
Erythropoietin (EPO) has a highly conserved structure among mammals, and thus recombinant human EPO (rHuEPO) has biological activity in various species. This study explores the interspecies relationships of the pharmacokinetics (PK) and pharmacodynamics (PD) of rHuEPO. The PK parameters such as clearance (CL) and volume of distribution (V(ss)) after i.v.(More)
An array of adverse steroid effects was examined on a whole body, tissue, and molecular level. Groups of male adrenalectomized Wistar rats were subcutaneously implanted with Alzet mini-pumps giving zero-order release rates of 0, 0.1, and 0.3 mg/kg/h methylprednisolone for 7 days. The rats were sacrificed at various times during the 7-day infusion period. A(More)
A fourth-generation pharmacokinetic/pharmacodynamic (PK/PD) model for receptor/genemediated effects of corticosteroids was developed. Male adrenalectomized Wistar rats received a 50 mg/kg i.v. bolus dose of methylprednisolone (MPL). Plasma concentrations of MPL, hepatic glucocorticoid receptor (GR) messenger RNA (mRNA) and GR density, tyrosine(More)
The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEpo) were investigated in monkeys. A two-compartment model with dual input and nonlinear disposition could adequately characterize the PK of rHuEpo upon three intravenous and six s.c. administrations. The kinetic model suggests rapid zero-order absorption of part of(More)
The existence and maintenance of biological rhythms linked to the 24-h light-dark cycle are essential to the health and functioning of an organism. Although much is known concerning central clock mechanisms, much less is known about control in peripheral tissues. In this study, circadian regulation of gene expression was examined in rat skeletal muscle. A(More)