Effect of injection routes on pharmacokinetics and lactone/carboxylate equilibrium of 9-Nitrocamptothecin in rats.

Jun Chen, Qineng Ping, Jianxin Guo, Minling Liu, Baochang Cai

Index: Int. J. Pharm. 340(1-2) , 29-33, (2007)

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Abstract

Pharmacokinetics and lactone/carboxylate equilibrium of 9-Nitrocamptothecin (9-NC) were compared after intravenous (i.v.) and intramuscular (i.m.) injection at a dose of 1.5mg/kg 9-NC solution. The concentrations of three different forms of 9-NC, namely lactone, carboxylate and total 9-NC, were measured by HPLC analysis. Injection routes were demonstrated to have significant effect on pharmacokinetics of 9-NC. Compared with i.v. injection route, mean residence time (MRT) of 9-NC three forms was significantly prolonged following i.m. route (p<0.05). The AUC(0-infinity) ratios of i.m. to i.v. route were calculated to be 102+/-43%, 273+/-221% and 150+/-62% for lactone, carboxylate and total 9-NC, respectively. Compared with i.v. injection route, although AUC(0-infinity) was barely changed, MRT of lactone 9-NC was dramatically prolonged 4.5-fold after i.m. injection, which may account for the reported improved antitumor efficacy. However, the results of the present study also demonstrated that i.m. injection route increased both AUC(0-infinity) and MRT of carboxylate 9-NC more significantly. Since the carboxylate form of CPT analogs including 9-NC is associated with their unwanted toxicity, i.m. injection route might lead to severe toxicity compared with i.v. route. Lactone/carboxylate equilibrium was also significantly influenced by injection routes. Based on the AUC(0-infinity) measurements, the lactone 9-NC constituted 50+/-8% and 32+/-7% of circulating total 9-NC after i.v. or i.m. administration, respectively (p<0.01).