Studies On Pharmacokinetics And Toxicokinetics Of Bromotetrandrine, An Anticancer Drug

In the present study, traditional Chinese medicine tetrandrine and its 5-bromized derivative bromotetrandrine were studied and evaluated through the combination of pharmacokinetics, toxicokinetics and metabonomincs method by which toxic markers were searched. This study is an important part of National 973 Plan Foundation of China (No. 2004BC518902) and Tianjin Development Plan of Science and Technology (05YFJZJC01100). Results with both scientific and practical significance were listed as follows:1. A rapid and sensitive liquid chromatography-tandem mass spectrometric method (LC/MS/MS) for the determination of tetrandrine in rat plasma has been developed, fully validated and successfully applied to a pharmacokinetic study in Sprague-Dawley (S.D.) rats after a single oral administration. The result showed that the metabolism of tetrandrine in both male and female rats was best fitted to one-compartment model.2. A rapid and sensitive liquid chromatography-tandem mass spectrometric method (LC/MS/MS) for the determination of bromotetrandrine in rat plasma has been developed, fully validated and successfully applied to a pharmacokinetic study in Sprague-Dawley (S.D.) rats after a single oral administration. The result exhibited sexual difference in the pharmacokinetics of bromotetrandrine between male and female rats, though its metabolism in both male and female rats was best fitted to one-compartment model.3. Single-dose and multi-dose toxicokinetic study, as well as toxicological study of both tetrandrine and bromotetrandrine were done in S.D. rats for evaluating kinetic properties and repeated dose safety for the two drugs. Results of single-dose toxicokinetic studies showed that at the dose that might induce toxicity, kinetic parameters of both tetrandrine and bromotetrandrine changed in rats. Multi-dose toxicokinetic studies recorded the changing states of tetrandrine and bromotetrandrine concentration in rat plasma, and demonstrated that after multiple administration of the two drugs at the dose that might induce toxicity, the metabolism of tetrandrine and bromotetrandrine were both changed in rats. Determination of blood biochemical parameters and tissue pathological slices results showed that both tetrandrine and bromotetrandrine exhibited liver, spleen and lung damage, the degree of all the damage was not alleviated after 6 days'recovery. 4. In the present study, we also did some primary metabonomic study for both tetrandrine and bromotetrandrine. LC-MS was developed for urine and plasma sample determination, and XCMS was exploited for data handling and analysis to research time-related changes of endogenous metabolic responses in rat urine and plasma to tetrandrine and bromotetrandrine stimuli, in order to find biomarkers in biochemical matrix. As a result 10 and 18 promising biomarkers were found in plasma and urine for tetrandrine, respectively. And 16 and 17 for bromotetrandrine in plasma and urine, respectively. Combined with the results of toxicokinetic studies, it was further confirmed that both tetrandrine and bromotetrandrine exhibited hepatotoxicity.