Use of a Physiologically Based Pharmacokinetic Model to Study the Time to Reach Brain Equilibrium:An Experimental Analysis of the Role of Blood-Brain Barrier Permeability,Plasma Protein Binding,and Brain Tissue Binding

摘要

This study was designed 1) to examine the effects of blood-brain barrier (BBB) permeability [quantified as permeability-surface area product (PS)],unbound fraction in plasma (f_u,plasma),and brain tissue (f_(u,brain) on the time to reach equilibrium between brain and plasma and 2) to investigate the drug discovery strategies to design and select compounds that can rapidly penetrate the BBB and distribute to the site of action.The pharmacokinetics of seven model compounds:caffeine,CP-141938 [methoxy-3-[(2-phenyl-piperadinyl-3-amino)-meth-yl]-phenyl-N-methyl-methane-sulfonamide],fluoxetine,NFPS [N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]sarcosine],propranolol,theobromine,and theophylline in rat brain and plasma after subcutaneous administration were studied.The in vivo log PS and log f_(u,brain) calculated using a physiologically based pharmacokinetic model correlates with in situ log PS (R~2 = 0.83) and in vitro log f_(u,brain) (R~2 = 0.69),where the in situ PS and in vitro f_(u brain) was determined using in situ brain per-fusion and equilibrium dialysis using brain homogenate,respectively.The time to achieve brain equilibrium can be quan-titated with a proposed parameter,intrinsic brain equilibriumhalf-life [f= V_bln2/(PS centre dot1/2eq,inf_(u,brain)].where V_b is the physio-logical volume of brain.The in vivo log t_(1/2eq,in) does not correlate with in situ log PS (R~2 < 0.01) but correlates inversely with log(PS centre dot f_(Uibrain)) (R~2 = 0.85).The present study demonstrates that rapid brain equilibration requires a combination of high BBB permeability and low brain tissue binding.A high BBB permeability alone cannot guarantee a rapid equilibration.The strategy to select compounds with rapid brain equilibration in drug discovery should identify compounds with high BBB permeability and low nonspecific binding in brain tissue.