The Pharmacokinetic Study Of 9-nitrocamptothecin-20-O-Propionate In Rat Plasma

Camptothecin(CPT)is a natural alkaloid isolated from Camptotheca acuminata.Camptothecin has been widespread concern due to its strong anti-tumor activity.9-nitrocamptothecin-20-O-propionate and 9-nitro-camptothecin are bioactive derivatives of camptothecin.9-nitrocamptothecin-20-O-propionate is the esterified product of 9-nitro-camptothecin,by stabilizing the structure of the lactone ring to reduce the toxicity.In the present study,the antitumor activity of 9-nitrocamptothecin-20-O-propionate and 9NC against four different cancer cells was tested in vitro.Further the pharmacokinetic studies of 9-nitrocamptothecin-20-O-propionate and its metabolite 9NC were demonstrated in rat.To elucidate the potential activity of 9-nitrocamptothecin-20-O-propionate and 9-nitro-camptothecin,we tested their antitumor activity against four cancer cell lines,including 2774(human ovarian cancer cell line),HT29(human colon cancer cell line),AGS(human prostate carcinoma cell line)and NCI-H520(human lung cancer cell line),compared with Camptothecin.Compared with the Camptothecin,the cytotoxic activity of the original drug 9-nitrocamptothecin-20-O-propionate is relatively low,but the cytotoxic activity of 9-nitro-camptothecin are better,especially for the AGS,the cytotoxic activity of 9-nitro-camptothecin was even higher than Camptothecin.9-nitro-camptothecin was identified as the major metabolite of 9-nitrocamptothecin-20-O-propionate in rat plasma by HPLC/photodiode array detection(PDA)and LC-MS/MS analysis.An LC-MS/MS method was developed to quantitatively determine 9-nitrocamptothecin-20-O-propionate and 9-nitro-camptothecin in rat plasma.The precursor/product transitions(m/z)were 450.03→ 362.00 and 450.03→376.00 for 9-nitrocamptothecin-20-O-propionate,394.06→ 304.10 and 394.06→ 350.10 for 9-nitro-camptothecin,respectively.The method was simple,quickly,accurate and precise,selectivity enough and has been successfully applied to the pharmacokinetic study.The pharmacokinetic study of 9-nitrocamptothecin-20-O-propionate and its metabolite 9-nitro-camptothecin in rat plasma was investigated after after intravenous(i.v.)administration at a dose of 10 mg·kg-1.After i.v.administration,the level of 9-nitrocamptothecin-20-O-propionate reached the maximum concentration.9-nitro-camptothecin concentration reached the maximum within the 30-40 min post-administration of the dose,and after 6h that 9-nitro-camptothecin level declined promptly.The total amount of 9-nitro-camptothecin was only 20%of 9-nitrocamptothecin-20-O-propionate according to the AUC0-24h.