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Unbound Drug Concentration in Brain Homogenate and Cerebral Spinal Fluid at Steady State as a Surrogate for Unbound Concentration in Brain Interstitial Fluid

Roche Palo Alto, Palo Alto, California

The objective of the present study was to examine the accuracy of using unbound brain concentration determined by a brain homogenate method (C_ub), cerebral spinal fluid concentration (C_CSF), and unbound plasma concentration (C_up) as a surrogate for brain interstitial fluid concentration determined by brain microdialysis (C_m). Nine compounds—carbamazepine, citalopram, ganciclovir, metoclopramide, N-desmethylclozapine, quinidine, risperidone, 9-hydroxyrisperidone, and thiopental—were selected, and each was administered as an intravenous bolus (up to 5 mg/kg) followed by a constant intravenous infusion (1–9 mg/kg/h) for 6 h in rats. For eight of the nine compounds, the C_ubs were within 3-fold of their C_m; thiopental had a C_m 4-fold of its C_ub. The C_CSFs of eight of the nine compounds were within 3-fold of their corresponding C_m; 9-hydroxyrisperidone showed a C_CSF 5-fold of its C_m. The C_ups of five of the nine compounds were within 3-fold of their C_m; four compounds (ganciclovir, metoclopramide, quinidine, and 9-hydroxyrisperidone) had C_ups 6- to 14-fold of their C_m. In conclusion, the C_ub and C_CSF were within 3-fold of the C_m for the majority of the compounds tested. The C_ups were within 3-fold of C_m for lipophilic non–P-glycoprotein (–P-gp) substrates and greater than 3-fold of C_m 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.

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