Study On The Pharmacokinetics And Tissue Distribution Of CPT8, A Camptothecin Analg

Due to camptothecin (CPT) is poor solubility and high toxicity, this topic aims at enhancing improve water solubility, increasing stability and decreasing the antitumor activity in blood of CPT. According to the research of CPT structure-activity relationship, the research improved anti-cancer activity at CPT10of its structure on the modified, in an attempt to improve water solubility, decrease the antitumor activity. Structure modification mainly adopted10-hydroxycamptothecine (HCPT) nuclear parent nucleophilic group, in alkaline conditions occur with pyridine nucleophilic substitution reaction. According to the evaluation in virto, CPT8can restrain the activity of Topol and the proliferation of tumor, respectively. Meanwhile, CPT8can inhibit the growth of S180tumor. In this study, the pharmacokinetics and tissue distribution of camptothecin derivatives CPT8were further reported by using high-performance liquid chromatography (HPLC) and liquid chromatography tandem mass spectrometry (LC-MS/MS).By K2CO3catalyzing condition, the nucleophilic group of the10-HCPT reacted with pyridine by the reaction of nucleophilic substitution. The products, CPT8, were determined by ’H NMR, IR, and MS.LC-MS-MS assay was established for determining the CPT8concentration in plasma after oral administration in mice. The retention times of CPT8and IS were at2.63min and3.06min. The calibration curve was linear over the range of2.5-2500ng/mL (r2>0.993) in rat plasma. The lowest concentration of2.5ng/mL with R.S.D<20%was taken with LLOQ. The extraction recovery from plasma and tissues was in the range of91.23%-105.36%. The range of inter-day and intra-day is0.21%and7.25%, respectively. The stability range is from84.12%to108.15%. The pharmacokinetics results showed that after oral administration of different dose50mg/kg of CPT8, the area under plasma concentration curve (AUCo→tand AUC0-∞) of CPT was181.76μg min/ml and189.03μg min/ml. The terminal half-life (t1/2) was approximately109.29min, and the clear ration is264.506L/kg/min.Moreover, LC-MS-MS assay was established for determining the CPT8concentration in various tissues after oral administration in mice. The method showed good linearity, precision and accuracy, recovery, matrix effect, and stability. Tissue distribution of CPT8was evaluated after a single oral administration (50mg/kg), after30min administration of CPT8; CPT8was mainly distributed in small intestine. Following180min of CPT8administration, most of the tissues contain CPT8. The results showed a widely distribution in small intestine, plasma, heart, kidney, spleen, liver, and lung. Following720min of CPT8administration, the CPT8had being cleared gradually. Calculated the AUC of CPT8in different tissues, the high distribution in lung and heart probable meant that the CPT8have strong effect on treating the lung cancer in clinical treatment.In summary, through animal experiments, the pharmacokinetic parameters were investigated after a single oral administration. CPT8concentration was studied in different tissues after oral administration. The resulting information about CPT8will provide the basis for clinical trials.