Abstract

This study was conducted to assess the utility of unbound brain EC₅₀ (EC_50,u) as a measure of in vivo potency for centrally active drugs. Seven μ-opioid agonists (alfentanil, fentanyl, loperamide, methadone, meperidine, morphine, and sufentanil) were selected as model central nervous system drugs because they elicit a readily measurable central effect (antinociception) and their clinical pharmacokinetics/pharmacodynamics are well understood. Mice received an equipotent subcutaneous dose of one of the model opioids. The time course of antinociception and the serum and brain concentrations were determined. A pharmacokinetic/pharmacodynamic model was used to estimate relevant parameters. In vitro measures of opioid binding affinity (K_i) and functional activity [EC₅₀ for agonist stimulated guanosine 5′-O-(3-[³⁵S]thio)triphosphate binding] and relevant clinical parameters were obtained to construct in vitro-to-preclinical and preclinical-to-clinical correlations. The strongest in vitro-to-in vivo correlation was observed between K_i and unbound brain EC_50,u (r² ∼ 0.8). A strong correlation between mouse serum and human plasma EC₅₀ was observed (r² = 0.949); the correlation was improved when corrected for protein binding (r² = 0.995). Clinical equipotent i.v. dose was only moderately related to K_i. However, estimates of ED₅₀ and EC₅₀ (total serum, unbound serum, total brain, and unbound brain) were significant predictors of clinical equipotent i.v. dose; the best correlation was observed for brain EC_50,u (r² = 0.982). For each opioid, brain equilibration half-life in mice was almost identical to the plasma effect-site equilibration half-life measured clinically. These results indicate that the mouse is a good model for opioid human brain disposition and clinical pharmacology and that superior in vitro-to-preclinical and preclinicalto-clinical correlations can be achieved with relevant unbound concentrations.