title: Revealing the Neuroendocrine Response After Remoxipride Treatment Using Multi-Biomarker Discovery and Quantifying It by PK/PD Modeling.
abstract: To reveal unknown and potentially important mechanisms of drug action, multi-biomarker discovery approaches are increasingly used. Time-course relationships between drug action and multi-biomarker profiles, however, are typically missing, while such relationships will provide increased insight in the underlying body processes. The aim of this study was to investigate the effect of the dopamine D2 antagonist remoxipride on the neuroendocrine system. Different doses of remoxipride (0, 0.7, 5.2, or 14 mg/kg) were administered to rats by intravenous infusion. Serial brain extracellular fluid (brainECF) and plasma samples were collected and analyzed for remoxipride pharmacokinetics (PK). Plasma samples were analyzed for concentrations of the eight pituitary-related hormones as a function of time. A Mann-Whitney test was used to identify the responding hormones, which were further analyzed by pharmacokinetic/pharmacodynamic (PK/PD) modeling. A three-compartment PK model adequately described remoxipride PK in plasma and brainECF. Not only plasma PRL, but also adrenocorticotrophic hormone (ACTH) concentrations were increased, the latter especially at higher concentrations of remoxipride. Brain-derived neurotropic factor (BDNF), follicle stimulating hormone (FSH), growth hormone (GH), luteinizing hormone (LH), and thyroid stimulating hormones (TSH) did not respond to remoxipride at the tested doses, while oxytocin (OXT) measurements were below limit of quantification. Precursor pool models were linked to brainECF remoxipride PK by Emaxdrug effect models, which could accurately describe the PRL and ACTH responses. To conclude, this study shows how a multi-biomarker identification approach combined with PK/PD modeling can reveal and quantify a neuroendocrine multi-biomarker response for single drug action.
authors: Systems Pharmacology, Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, PO box 9502, 2300 RA, Leiden, The Netherlands.
authors: Willem J
authors: WJ
authors: van den Brink
authors: Systems Pharmacology, Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, PO box 9502, 2300 RA, Leiden, The Netherlands.
authors: Yin C
authors: YC
authors: Wong
authors: Systems Pharmacology, Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, PO box 9502, 2300 RA, Leiden, The Netherlands.
authors: Berfin
authors: B
authors: Gülave
authors: Systems Pharmacology, Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, PO box 9502, 2300 RA, Leiden, The Netherlands.|Certara QSP, Canterbury Innovation House, Canterbury, UK.
authors: Piet H
authors: PH
authors: van der Graaf
authors: Systems Pharmacology, Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, PO box 9502, 2300 RA, Leiden, The Netherlands. ecmdelange@lacdr.leidenuniv.nl.
authors: Elizatbeth C M
authors: EC
authors: de Lange
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis* / Q000097:blood; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000737:chemistry; D007262:Infusions, Intravenous; D008297:Male; D017551:Microdialysis; D008954:Models, Biological; D009490:Neurosecretory Systems / Q000187:drug effects* / Q000378:metabolism; D017208:Rats, Wistar; D017330:Remoxipride / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D065127:Dopamine D2 Receptor Antagonists; D017330:Remoxipride
keywords: CNS; blood–brain barrier; dose–response; hormones; pharmacokinetic/pharmacodynamic models