@article {Liu787, author = {Xingrong Liu and Kristine Van Natta and Helen Yeo and Olga Vilenski and Paul E. Weller and Philip D. Worboys and Mario Monshouwer}, title = {Unbound Drug Concentration in Brain Homogenate and Cerebral Spinal Fluid at Steady State as a Surrogate for Unbound Concentration in Brain Interstitial Fluid}, volume = {37}, number = {4}, pages = {787--793}, year = {2009}, doi = {10.1124/dmd.108.024125}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The objective of the present study was to examine the accuracy of using unbound brain concentration determined by a brain homogenate method (Cub), cerebral spinal fluid concentration (CCSF), and unbound plasma concentration (Cup) as a surrogate for brain interstitial fluid concentration determined by brain microdialysis (Cm). Nine compounds{\textemdash}carbamazepine, citalopram, ganciclovir, metoclopramide, N-desmethylclozapine, quinidine, risperidone, 9-hydroxyrisperidone, and thiopental{\textemdash}were selected, and each was administered as an intravenous bolus (up to 5 mg/kg) followed by a constant intravenous infusion (1{\textendash}9 mg/kg/h) for 6 h in rats. For eight of the nine compounds, the Cubs were within 3-fold of their Cm; thiopental had a Cm 4-fold of its Cub. The CCSFs of eight of the nine compounds were within 3-fold of their corresponding Cm; 9-hydroxyrisperidone showed a CCSF 5-fold of its Cm. The Cups of five of the nine compounds were within 3-fold of their Cm; four compounds (ganciclovir, metoclopramide, quinidine, and 9-hydroxyrisperidone) had Cups 6- to 14-fold of their Cm. In conclusion, the Cub and CCSF were within 3-fold of the Cm for the majority of the compounds tested. The Cups were within 3-fold of Cm for lipophilic non{\textendash}P-glycoprotein ({\textendash}P-gp) substrates and greater than 3-fold of Cm for hydrophilic or P-gp substrates. The present study indicates that the brain homogenate and cerebral spinal fluid methods may be used as surrogate methods to predict brain interstitial fluid concentrations within 3-fold of error in drug discovery and development settings. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/37/4/787}, eprint = {https://dmd.aspetjournals.org/content/37/4/787.full.pdf}, journal = {Drug Metabolism and Disposition} }