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.