Antitumor efficacy, toxicity and pharmacokinetics of 9-nitrocamptothecin: role of lactone ratio.
OBJECTIVE
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.
College of Pharmacy, Nanjing University of Chinese Medicine, 138# Xianlin Road, Nanjing, 210023, People's Republic of China, chenjun75@163.com.
Jun
J
Chen
Rong-Rong
RR
Hu
Xi-Xiong
XX
Yang
Wei
W
Gu
Rong
R
Tian
Fang
F
Gong
Lei
L
Luo
Fang
F
Fang
Zhi-Peng
ZP
Chen
Bao-Chang
BC
Cai
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D007783:Lactones / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D012510:Sarcoma 180 / Q000188:drug therapy* / Q000473:pathology; D014018:Tissue Distribution; D018675:Toxicity Tests
D000970:Antineoplastic Agents; D007783:Lactones; C079905:rubitecan; D002166:Camptothecin