Open AccessBlood‐Based Biomarkers of Quinpirole Pharmacology: Cluster‐Based PK / PD and Metabolomics to Unravel the Underlying Dynamics in Rat Plasma and Brain
Author(s) -
Brink Willem J.,
Hartman Robin,
Berg DirkJan,
Flik Gunnar,
GonzalezAmoros Belén,
Koopman Nanda,
ElassaisSchaap Jeroen,
Graaf Piet Hein,
Hankemeier Thomas,
Lange Elizabeth C.M.
Publication year - 2019
Publication title -
cpt: pharmacometrics and systems pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.53
H-Index - 37
ISSN - 2163-8306
DOI - 10.1002/psp4.12370
Subject(s) - pharmacology , pharmacokinetics , dopamine , quinpirole , microdialysis , pharmacodynamics , central nervous system , drug , agonist , chemistry , blood–brain barrier , extracellular fluid , blood plasma , metabolomics , medicine , extracellular , dopamine receptor , receptor , biochemistry , chromatography
A key challenge in the development of central nervous system drugs is the availability of drug target specific blood‐based biomarkers. As a new approach, we applied cluster‐based pharmacokinetic/pharmacodynamic ( PK / PD ) analysis in brain extracellular fluid (brain ECF ) and plasma simultaneously after 0, 0.17, and 0.86 mg/kg of the dopamine D 2/3 agonist quinpirole ( QP ) in rats. We measured 76 biogenic amines in plasma and brain ECF after single and 8‐day administration, to be analyzed by cluster‐based PK / PD analysis. Multiple concentration‐effect relations were observed with potencies ranging from 0.001–383 nM . Many biomarker responses seem to distribute over the blood‐brain barrier (BBB). Effects were observed for dopamine and glutamate signaling in brain ECF , and branched‐chain amino acid metabolism and immune signaling in plasma. Altogether, we showed for the first time how cluster‐based PK / PD could describe a systems‐response across plasma and brain, thereby identifying potential blood‐based biomarkers. This concept is envisioned to provide an important connection between drug discovery and early drug development.