Comparative brain tissue distribution of camptothecin and topotecan in the rat

Purpose: The primary objective of this investigation was to compare the extent of brain distribution of the lactone and the carboxylate forms of camptothecin (CPT) and topotecan (TPT) in awake freely moving rats. Methods: The plasma concentration-time profiles of the lactone and the carboxylate forms of CPT and TPT were determined simultaneously after a single i.v. administration of the lactone form of each drug. Also, the brain extracellular fluid (ECF) concentration-time profiles were characterized utilizing the microdialysis technique. This technique allowed serial sampling of the brain ECF in awake rats. Results: CPT-lactone in plasma declined biexponentially with a terminal half-life of 102 ± 25.2 min. During the elimination phase, the plasma concentration of CPT-carboxylate was approximately ten times the concentration of CPT-lactone. The brain ECF to plasma distribution ratio measured 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 CPT-carboxylate. The terminal half-life for TPT-lactone was 64.0 ± 9.4 min. During the elimination phase, the TPT-carboxylate concentration was higher than that of TPT-lactone 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 and TPT are distributed to the brain ECF most probably by passive diffusion across the blood-brain barrier. Although the brain ECF to plasma distribution ratio for CPT-lactone was higher than that for TPT-lactone, the brain ECF concentrations of TPT-lactone were significantly higher than the CPT-lactone brain ECF concentrations. The relatively high brain ECF to plasma distribution ratio of these two drugs makes them potential candidates for first-line treatment of CNS tumors. Received: 4 May 1998 / Accepted: 5 August 1998