Purpose: Since the carboxylate form could be regarded as a possible "source" of lactone form, the optimum ratio of lactone should be determined for the administration of camptothecin (CPT) analogues such as 9-nitrocamptothecin (9-NC).
Methods: 9-NC solutions with different lactone ratios (100, 75, 50, 25 and 0 %) were obtained by the change of pH. The resultant 9-NC solution and corresponding blank solvent were intravenously injected to mice to evaluate toxicity. The S180 tumor-bearing mice were intravenously administered 9-NC solutions with different lactone ratios, and the antitumor efficacy and toxicity were compared. The tissue distribution of lactone and total (the total of lactone and carboxylate forms) 9-NC was also investigated as a function of lactone ratio.
Results: Toxicity of 9-NC was found to be increased with the increase in lactone ratio. The tumor inhibitory rates of 9-NC solution were determined to be 64.17, 60.43, 42.78, 41.71 and 8.60 % for 100, 75, 50, 25 and 0 % lactone ratio, respectively. The lactone stability of 9-NC in most tissues was found to be higher than in plasma. In tumor and plasma, whether for lactone or total 9-NC AUC values, there was no difference between 100 and 75 % groups.
Conclusions: Although carboxylate form of CPTs is inactive, the administration of carboxylate form in an appropriate ratio is active as a result of its conversion to lactone form in vivo.