Second - (4 - Chloro-benzoyl Hydroxamic Acid) And Two N-butyl-co Tin (dbdct), Liposomes And In Vivo Pharmacokinetic Studies

Di-n-butyl-di-(4-chlorobenzohydroxamato) tin (IV) (DBDCT) is a new antitumor compound with high activity and relatively low bioavailability. It could distribute and be eliminated rapidly in rat with a short half-time(T1/2) value. In this paper the liposome of DBDCT (DBDCT-L) was first prepared in order to improve the pharmacokinetics characteristics and finally to raise its therapeutic indexes.In order to control the quality of DBDCTL, the method for determination of DBDCT quality by HPLC and for determination of encapsulation efficiency of DBDCT-L by Sephadex G-50 minicolumn using centrifugation technique were established. The encapsulation efficiency was calculated by comparing the amount of drug present in the final liposome suspension with that present prior to the removal of the non-incorporated drug. The entrapping efficiency is 67.2%.Liposomes of DBDCT were prepared by thin film evaporation–extrusion technique. Orthogonal design was adopted to the formulation of DBDCT liposome on the basis of the score of the entrapment efficiency. According to the entrapment efficiency, various factors were studied. The orthogonal experimental design was chosen to optimize the condition of preparation DBDCT-L. The analysis showed (PC) 200mg, (PC/CH) 6:1, (PBS) 10ml, which were the optimal formulation.The size, size distribution and shape of all batches of liposomes were determined using dynamic light scattering and negative staining electron microscopy. The mean diameter of the liposomes loaded with DBDCT was 128.3nm.A comparison study of the pharmacokinetics and tissue distribution after intravenous administrations of the DBDCT-L with the corresponding free DBDCT to rats was investigated. Comparing with the free DBDCT, the DBDCT-L showed slower clearance, increased half-time and larger AUC value than those of the free DBDCT after intravenous administration to rats. Significant differences were observed in heart, liver, spleen, lung, kidney, brain and adrenal gland after administration of DBDCT-L and the free DBDCT. However, the distribution in the spleen, liver, lung and kidney of DBDCT-L was higher than those of the free DBDCT, especially the concentration distribution in liver is the highest which may be associated with the enhanced antitumor activity and indicated the possible target release of the drug.The acute toxicity studies showed that the LD50 value of the DBDCT-L is higher than that of the free DBDCT. The further in vivo antitumor tests in mice showed that DBDCT-L displayed higher in vivo antitumor activity against the hepatocellular carcinoma H22 than those of the free DBDCT, and indicated that the liposomes could prolong the action-time of DBDCT in the system circulation, change its distribution in rats in vivo, reduce the acute toxicity and finally raise the antitumor activity.