Comparative brain tissue distribution of camptothecin and topotecan in therat

Purpose: The primary objective of this investigation was to compare the ext ent of brain distribution of the lactone and the carboxylate forms of campt othecin (CPT) and topotecan (TPT) in awake freely moving rats. Methods: The plasma concentration-time profiles of the lactone and the carboxylate form s of CPT and TPT were determined simultaneously after a single i.v. adminis tration of the lactone form of each drug. Also, the brain extracellular flu id (ECF) concentration-time profiles were characterized utilizing the micro dialysis technique. This technique allowed serial sampling of the brain ECF in awake rats. Results: CPT-lactone in plasma declined biexponentially wit h a terminal half-life of 102 +/- 25.2 min. During the elimination phase, t he plasma concentration of CPT-carboxylate was approximately ten times the concentration of CPT-lactone. The brain ECF to plasma distribution ratio me asured as the ratio of the AUC in the brain ECF to the AUC in plasma was 0. 51 +/- 0.08 for CPT-lactone, and 0.26 +/- 0.21 for CP-T-carboxylate. The te rminal half-life for TPT-lactone was 64.0 +/- 9.4 min. During the eliminati on phase, the TPT-carboxylate concentration was higher than that of TPT-lac tone but the carboxylate to lactone concentration ratio was much lower than that of CPT. The brain ECF to plasma distribution ratio was 0.38 +/- 0.12 for TPT-lactone, and 0.21 +/- 0.06 for TPT-carboxylate. Conclusions: CPT an d TPT are distributed to the brain ECF most probably by passive diffusion a cross the blood-brain barrier. Although the brain ECF to plasma distributio n ratio for CPT-lactone was higher than that for TPT-lactone, the brain ECF concentrations of TPT-lactone were significantly higher than the CPT-lacto ne brain ECF concentrations. The relatively high brain ECF to plasma distri bution ratio of these two drugs makes them potential candidates for first-l ine treatment of CNS tumors.