Blood-Based Biomarkers of Quinpirole Pharmacology: Cluster-Based PK/PD and Metabolomics to Unravel the Underlying Dynamics in Rat Plasma and Brain.

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 (brainECF ) and plasma simultaneously after 0, 0.17, and 0.86 mg/kg of the dopamine D2/3 agonist quinpirole (QP) in rats. We measured 76 biogenic amines in plasma and brainECF 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 brainECF , 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.