Pharmacokinetics, Tissue Distribution, And Metabolism Of Natural Anticancer Agent Yuanhuacine In Rabbits

The investigation on malignant tumor epidemic trend has shown that tumor incidence has ranked 2^nd in the causes of death over the world whilst rank 1^st in China.Chemotherapy,a systemic therapia,had been proved to be the most crucial tool in tumor treatment.Natural antitumor drug had been evaluated as the vital part of chemotherapy medication.Yuanhuacine(YHC) is an anti-cancer agent,which belongs to daphne diterpene ortho-esters extracted from Daphne genkwa Sieb et Zucc.The potent inhibitory activity against DNA topoisomerase I is probably one of its anticancer mechanisms.Consequently, the pharmacokinetics,tissue distribution and metabolism following single-dose intravenous administration of YHC in rabbits were studied in the present investigation.Analytical method for the quantification of yuanhuacine and its injection was established. The relative correction factors of yuanhuadine and orthor-ester ring-open compound,which are the relative substance of yuanhuacine,were determined,respectively.Stability test results indicate that yuanhuacine and its injection are both not influenced by temperature and humidity,but will be influenced by illumination.Validated liquid chromatography/tandem mass spectrometry method was developed for quantitative determination of YHC and identification of its metabolites in pharmacokinetics,tissue distribution and metabolism studies in rabbit plasma herein.The results showed that YHC pharmacokinetics was best fitted to a two-compartment model with the elimination half-life t_1/2(β) of 11.1 h following a single intravenous administration.Tissue distribution test indicated that YHC showed no special affinity to any tissues.The main putative metabolites were suggested to be M392Ⅰ, M392Ⅱand M390,due to the ortho-ester group and aromatic ester bond being cleaved off simultaneously in Phase I metabolic process.The major residues in the excreta of rabbit were YHC metabolites with less than 0.5%parent drug present This investigation might be beneficial contribution to further studies of yuanhuacine in clinical pharmacokinetic studies.