title: Effect of injection routes on pharmacokinetics and lactone/carboxylate equilibrium of 9-Nitrocamptothecin in rats.
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).
authors: College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210029, People's Republic of China.
authors: Jun
authors: J
authors: Chen
authors: Qineng
authors: Q
authors: Ping
authors: Jianxin
authors: J
authors: Guo
authors: Minling
authors: M
authors: Liu
authors: Baochang
authors: B
authors: Cai
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001711:Biotransformation; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002264:Carboxylic Acids / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D007273:Injections, Intramuscular; D007275:Injections, Intravenous; D007783:Lactones / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002264:Carboxylic Acids; D007783:Lactones; C079905:rubitecan; D002166:Camptothecin