title: Pharmacokinetics of lactone, carboxylate and total 9-nitrocamptothecin with different doses and administration routes in rats.
abstract: 9-Nitrocamptothecin (9-NC) is a newly developed poorly soluble derivative of camptothecin and has a wide spectrum of anticancer activity in preclinical evaluation. The effects of the dose and administration route on pharmacokinetics and lactone/carboxylate equilibrium of 9-NC were studied in rats. A single intravenous dose of 1.5, 3 or 6 mg/kg of 9-NC solution was given to male rats (n = 6 per dose level). In another study, a single dose of 6 mg/kg 9-NC solution was given orally to rats (n = 6). Plasma samples were drawn at predetermined intervals and the concentrations of lactone, carboxylate and total 9-NC were determined by a validated HPLC method. Pharmacokinetic analysis was performed using non-compartmental analysis. Analysis of variance showed that the pharmacokinetic characteristics of lactone, carboxylate and total 9-NC were all independent of dose (p > 0.05). Based on the AUC measurements, the lactone 9-NC constituted 52% +/- 4%, 49% +/- 6% and 55% +/- 6% of the circulating total 9-NC in rats after intravenous administration of 1.5, 3, 6 mg/kg 9-NC solution, respectively. After oral administration of 6 mg/kg, the pharmacokinetics parameters were significantly different from those of intravenous administration at the same dose (p < 0.05). The lactone ratio was 60% +/- 14%. The absolute bioavailability of lactone and total 9-NC were calculated to be 23.4% and 22.7%, respectively. In conclusion, the pharmacokinetics of lactone, carboxylate and total 9-NC are not dose-dependent. Lactone, carboxylate and total 9-NC are poorly absorbed following oral administration. Both the dose and the route of administration have little effect on the lactone/carboxylate equilibrium of 9-NC in rats in vivo. But the route of administration plays an important part on the pharmacokinetics of 9-NC.
authors.affiliation: Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210038, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Qineng
authors.initials: Q
authors.lastname: Ping
authors.forename: Jianxin
authors.initials: J
authors.lastname: Guo
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Chu
authors.forename: Mingmei
authors.initials: M
authors.lastname: Song
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002264:Carboxylic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007783:Lactones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D007783:Lactones; C079905:rubitecan; D002166:Camptothecin