Pharmacokinetics of 9-nitro-20(S)-camptothecin in rats

To study the pharmacokinetics and the excretion of 9-nitro-20(S)-camptothecin (9-NC) in rats.

Each rat was given a single dose at random by iv or ig administration. Serial plasma and excreta samples were collected and the pharmacokinetic behavior of 9-NC in rats was characterized by specific liquid chromatographic assays. Individual 9-NC plasma-concentration data were analyzed by both noncompartmental and compartmental analysis. For dose proportionality, AUC- and Cmax-dose relationships were evaluated by linear regression, and t1/2 and CLtot were compared by an analysis of variance model. Also, the excretion of the parent drug was estimated.

After iv administration of 9-NC at the doses of 1.5, 3, and 6 mg/kg, the t1/2 values for 9-NC were estimated to be 0.5, 0.5, and 0.7 h, respectively, and the mean AUC0-t values were 633, 1606, and 3011 h.microg.L(-1), respectively. 9-NC was rapidly absorbed, reaching mean Cmax of 203, 417, and 1150 microg/L at Tmax of 0.3, 0.2, and 0.3 h at the doses of 3, 6, and 12 mg/kg, respectively. The mean AUC0-t values were 269, 439, and 881 h.microg.L(-1), and the mean t1/2 values were 1.7, 0.9, and 0.9 h, respectively. The absolute oral bioavailability of 9-NC was calculated to be 14.6 %, which was consistent with the ratio of the total cumulative excretion in the urine and bile by ig to that by iv injection.

The kinetic process of 9-NC in rats in vivo was best fitted to a two-compartmental model. For iv administration, the pharmacokinetics are not dose-dependent. The oral bioavailability of 9-NC was low. Renal excretion was the primary elimination route of the parent drug after iv administration, however, after ig administration the unchanged drug was largely excreted in the feces because of the poor absorption.