Quantification of Neocortical Slice Diffusion Characteristics Using Pharmacokinetic and Pharmacodynamic Modelling

Pharmacological brain slice experiments are complicated by the need to ensure adequate drug delivery deep into the healthy layers of the tissue. Because tissue slices have no blood supply, this is achieved solely by passive drug diffusion. The aim of this study was to determine whether pharmacokinetic/pharmacodynamic (PKPD) modeling could be adapted to estimate drug diffusion times in neocortical brain slices. No-magnesium seizure-like event (SLE) activity was generated in 41 slices (400 μm). Two anesthetic agents, etomidate (24 μM, n = 14) and thiopental (250 μM, n = 14), and magnesium ions (n = 13) were delivered to effect reversible reductions in SLE frequency. Concentration-effect hysteresis loops were collapsed using a first order rate constant model and equilibrium half-lives (t(1/2)K(e0)) derived. The t(1/2)K(e0) values obtained were consistent with expectations. The median (range) t(1/2)K(e0) of 83.1 (19.4–330.1) min for etomidate is in keeping with its known slow diffusion into brain slice tissue. Values for etomidate and thiopental (111.8 (27.8–198.0) min) were similar, while magnesium had a significantly faster equilibration rate (t(1/2)K(e0) of 26.1 (8.6–77.0) min) compared to the anesthetics, as expected for a simple ion. In conclusion, PKPD modeling is a simple and practical method that can be applied to brain slice experiments for investigating drug diffusion characteristics.