Lactone Stability and Tissue Distribution of Free and Liposomal Encapsulated 9-Nitrocamptothecin in Rats Following Intravenous Injection

• Published in: Drug development and industrial pharmacy 2008-01, Vol.34 (8), p.853-859
• Main Authors: Chen, Jun, Cai, Baochang, Ping, Qineng, Liu, Minling, Guo, Jianxin
• Format: Article
• Language: English
• Subjects: 9-nitrocamptothecin; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Biological and medical sciences; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - blood; Camptothecin - pharmacokinetics; Chromatography, High Pressure Liquid; Drug Stability; General pharmacology; Injections, Intravenous; lactone; Lactones - administration & dosage; Lactones - blood; Lactones - pharmacokinetics; liposomes; Liver - metabolism; Male; Medical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Tissue Distribution
• ISSN: 0363-9045; 1520-5762
• DOI: 10.1080/03639040801928762

9-Nitrocamptothecin (9-NC) is a newly developed but poorly soluble derivative of camptothecin (CPT), which has a wide spectrum of anticancer activity in preclinical evaluation. Lactone moiety is a key structural feature for the antitumor activity of CPT analogs including 9-NC. Lactone stability versus time profiles of 9-NC in vivo following intravenous (i.v.) administration of free and liposomal encapsulated 9-NC has been investigated in this article. After i.v. injection of 9-NC solution, it was found that lactone stability of 9-NC in liver was the poorest in vivo and even worse than that in plasma. In other tissues, lactone stability of 9-NC was better than that in plasma. After liposomal encapsulation, both lactone and total 9-NC concentrations in reticuloendothelial system (RES) tissues, for example, spleen, liver, and lung, were significantly increased. In particular, liposomal encapsulation had a significant improving effect on the lactone stability of 9-NC in the liver. The lactone percentage was increased from 39.11 ± 16.93% to 65.57 ± 9.73% (p < .05) at 10 min and from 30.99 ± 6.54% to 51.22 ± 11.10% (p < .01) at 30 min. On the basis of these results, a theoretical explanation of lactone stability in vivo was discussed. In summary, liposomal encapsulation, which resulted in passive targeting and a significant improvement of lactone stability in the liver, might have clinical utility.