Dataset Information

Fingerprints of CNS drug effects: a plasma neuroendocrine reflection of D₂ receptor activation using multi-biomarker pharmacokinetic/pharmacodynamic modelling.

ABSTRACT:

Background and purpose

Because biological systems behave as networks, multi-biomarker approaches increasingly replace single biomarker approaches in drug development. To improve the mechanistic insights into CNS drug effects, a plasma neuroendocrine fingerprint was identified using multi-biomarker pharmacokinetic/pharmacodynamic (PK/PD) modelling. Short- and long-term D₂ receptor activation was evaluated using quinpirole as a paradigm compound.

Experimental approach

Rats received 0, 0.17 or 0.86 mg·kg^-1 of the D₂ agonist quinpirole i.v. Quinpirole concentrations in plasma and brain extracellular fluid (brain_ECF ), as well as plasma concentrations of 13 hormones and neuropeptides, were measured. Experiments were performed at day 1 and repeated after 7-day s.c. drug administration. PK/PD modelling was applied to identify the in vivo concentration-effect relations and neuroendocrine dynamics.

Key results

The quinpirole pharmacokinetics were adequately described by a two-compartment model with an unbound brain_ECF -to-plasma concentration ratio of 5. The release of adenocorticotropic hormone (ACTH), growth hormone, prolactin and thyroid-stimulating hormone (TSH) from the pituitary was influenced. Except for ACTH, D₂ receptor expression levels on the pituitary hormone-releasing cells predicted the concentration-effect relationship differences. Baseline levels (ACTH, prolactin, TSH), hormone release (ACTH) and potency (TSH) changed with treatment duration.

Conclusions and implications

The integrated multi-biomarker PK/PD approach revealed a fingerprint reflecting D₂ receptor activation. This forms the conceptual basis for in vivo evaluation of on- and off-target CNS drug effects. The effect of treatment duration is highly relevant given the long-term use of D₂ agonists in clinical practice. Further development towards quantitative systems pharmacology models will eventually facilitate mechanistic drug development.

SUBMITTER: van den Brink WJ

PROVIDER: S-EPMC6135786 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

Fingerprints of CNS drug effects: a plasma neuroendocrine reflection of D<sub>2</sub> receptor activation using multi-biomarker pharmacokinetic/pharmacodynamic modelling.

van den Brink Willem J WJ van den Berg Dirk-Jan DJ Bonsel Floor E M FEM Hartman Robin R Wong Yin-Cheong YC van der Graaf Piet H PH de Lange Elizabeth C M ECM

British journal of pharmacology 20180831 19

<h4>Background and purpose</h4>Because biological systems behave as networks, multi-biomarker approaches increasingly replace single biomarker approaches in drug development. To improve the mechanistic insights into CNS drug effects, a plasma neuroendocrine fingerprint was identified using multi-biomarker pharmacokinetic/pharmacodynamic (PK/PD) modelling. Short- and long-term D<sub>2</sub> receptor activation was evaluated using quinpirole as a paradigm compound.<h4>Experimental approach</h4>Rat ...[more]

PMID: 30051461

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Dataset Information

Fingerprints of CNS drug effects: a plasma neuroendocrine reflection of D₂ receptor activation using multi-biomarker pharmacokinetic/pharmacodynamic modelling.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Fingerprints of CNS drug effects: a plasma neuroendocrine reflection of D<sub>2</sub> receptor activation using multi-biomarker pharmacokinetic/pharmacodynamic modelling.

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Dataset Information

Fingerprints of CNS drug effects: a plasma neuroendocrine reflection of D2 receptor activation using multi-biomarker pharmacokinetic/pharmacodynamic modelling.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Fingerprints of CNS drug effects: a plasma neuroendocrine reflection of D&lt;sub&gt;2&lt;/sub&gt; receptor activation using multi-biomarker pharmacokinetic/pharmacodynamic modelling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Fingerprints of CNS drug effects: a plasma neuroendocrine reflection of D₂ receptor activation using multi-biomarker pharmacokinetic/pharmacodynamic modelling.

Fingerprints of CNS drug effects: a plasma neuroendocrine reflection of D<sub>2</sub> receptor activation using multi-biomarker pharmacokinetic/pharmacodynamic modelling.