Pharmacokinetics Studies On Some Pharmaceutical Preparations And Bone-targeting Compounds

Objectives: DDS (Drag Delivery system) and targeted drag can improve absorption and distribution of pharmaceuticals as well as reduce the toxicity and adverse effects of drags, prolong the duration of action, enhance the effect of treatment, improve the accessibility of drags that pharmaceutical reparations may become safe, effective, stable, controllable and easy to use. Pharmaceutical evaluation in vitro, however, tends to be blind, which can hardly account for bioavailability and target distribution in vivo. Pharmacokinetics has to be involved in the screening of prescriptions in the early stage in order to be able to develop pharmaceuticals with the desire pharmacokinetic properties. To optimize and modify prescriptions, it is necessary to provide in vivo evaluation results and get the feedback and at the same time the in vivo-in vitro relevance has to be established.Methods: 1.Pharmacokinetics Study on Naltrexone Microspheres Sustained-release Preparation in Rhesus monkeys: To establish and validate a method by LC/MS/MS determination Naltrexone and its metabolite Naltrexol in plasma, the Pharmacokinetics processes in Rhesus monkeys on three formations A B C which contained two dosages each were investigated in turn. 2. Comparison of Pharmacokinetics of Paclitaxel emulsion and Paclitaxel injection in Beagle dogs: a random, double-periods and self-crossover design and an internal standard quantitative method was established and validated to determine Paclitaxel in plasma by LC/MS/MS. 3. Evaluation of the bone-targeting characteristics of DHTBP in vivo: The quantitative method was established to determine the total quantify (DHT and DHTBP) through their hydrolysis product by LC/MS/MS. The states of two compounds in plasma and femoral bones were investigated and compared after i.v. equimolar DHT and DHTBP in rats.Results: 1. The data suggested that Naltrexone Microspheres Sustained-release Preparation A B C were all of sustained-releasing properties in vivo. According to the effective concentration at 1 ng/mL, among the 200mg/kg group. Formulation A was able to be sustained for about 18 days, B and C could be kept for almost 43 days on average. Among the 8 mg/kg group, Formulation A was able to be sustained for about 7 days, B and C could be kept for almost 35 days on average. Formulation A and B both had suddenly released in vivo, but not exactly for C. The time of sudden-release for A was 48h? and the maximum concentration at that moment was 91.8 ng/mL; As the same phenomenon for B was 0.5h and the maximum concentration was 153 ng/mL. However, the release process of Formulation C was suitable to zero-order kinetics. 2. The investigation demonstrated that the two preparations of paclitaxel were both fitted to two-compartment model. The main pharmacokinetic parameters of Paclitaxel emulsion and Paclitaxel injection were as follows: tl/2z were 5.07±1.30 and 4.62±0.976 (h); CLz were 15.1±2.43和10.1±2.35 (h·L^-1); Vz were 111±38.8 and 65.8±16.4 (L); C_max were 1416±162 and 2231±519 (μg·L^-1); AUC_0-11.33 were 2442±535 and 3753±771 (μg·h·L^-1 ); AUC_0-∞ were 2725±559 and 4163±922 (μg·h·L^-1) The AUC ratio of paclitaxel emulsion and reference preparation was 0.665±0.146. 3. The data demonstrated that DHTBP was better than its parent compound DHT on bone-targeting selectivity. After i.v. for 7days,the amount of DHTBP in femoral bone is nearly 22 times as the amount of DHT. During a week, the drug gradually released from femoral bone in the DHTBP group, but the DHT was not be able to be tested.Conclusion: 1. Naltrexone Microspheres Sustained-release Preparation C was of the best sustained-release character and suitable for further developed. 2. The two preparations of paclitaxel were both fitted to two-compartment model. The pharmacokinetic parameters AUC CLz Vz and Cmax of the two preparations are significantly different at the 0.05 level (Paired t-Test). There was no sex difference in Beagle dogs between the main pharmacokinetic parameters of the two preparations. 3. DHTBP was better than its parent compound DHT on bone-targeting selectivity. Pharmacokinetics is very useful for improvement of pharmaceutical evaluation and modification target compound.