| Object: To explore preclinical pharmacokinetic of the manufacture ofEpirubicin polybutylcyanoacylate nanoparticles(EPI-PBCA-NP) underthe optimiunal conditions, and to compare parameteres ofpharmacokinetic and the rate of protein binding with Epirubicin(EPI), soas to provide the safety and the availability for clinical rationaladministration(the dose of optimization, route of administration, time ofdosing interval and dosage form).Methods: The EPI-PBCA-NP was prepared with the emulsionpolymerization method and the particle diameter were determined byPCS, appearance were determined by electronmicroscope, entrapmentefficiency and quantity of drug-loaded were determined byhigh-performance chromatography. The twenty home rabbits were dividedinto four groups in random, five each. Every rabbit was put a pipe in itsjugular vein, then injected drugs and exsanguinated. The group ofEPI-PBCA-NP were divided into three groups according by givenEPI-PBCA-NP(corresponding EPI 2.65mg/kg, 5.3mg/kg and 8.83mg/kg), and the group of EPI were given EPI 5.3mg/kg to every rabbit. Allthe druges were diluted to 10ml, and were injected by the vein of thefringe of ear. One millilitre blood was drawed by pipe in rabbit's jugularvein at the time of 0.083, 0.167, 0.333, 0.5, 0.667, 1,2,4,6,9 and 12hours, then measure the concentration of EPI at every time, last calculatethe parameteres of pharmacokinetic by "DAS2.0" software.T he rate ofprotein binding of EPI and EPI-PBCA-NP was measured by equilibriumdialysis. Then analyse the parameteres of pharmacokinetic and the rate ofprotein binding of EPI and EPI-PBCA-NP with "SPSS 11.0" software.Result: The appearance of EPI-PBCA-NP was regular andwell-distributed, the mean of diametre was 135.5±16.8nm(n=15), themean of entrapment efficiency was 84.04±13.50%, and the mean ofquantity of drug-loaded was 16.65±2.35%. The measure ofhigh-performance chromatography. The linearity was obtained from 10 to 1200ug/L of EPI in plasma with a good correction coefficient(r=0.998, n=6). The RSD of interaday and interday validations were lessthen 8.5%, and RSD of the rcoveries were less than 9% for the low, middleand high concentrations of check samples. The pharmacokinetic of EPIand EPI-PBCA-NP in home rabbits were according to the three chambermodels. Compare to EPI, the T1/2αof EPI-PBCA-NP was 0.41 times, theT1/2βof EPI-PBCA-NP was 1.97 times, T1/2γof EPI-PBCA-NP was4.53 times, the clearness of new drug from blood(CL) was 0.46 times, thearea of under the curve(AUC(0-t)) was 1.74 times. According thePharmacokinetic statistical moment parameters, compare to the EPI, theMRT of EPI-PBCA-Np was 1.41 times, the T1/2z of EPI-PBCA-Npwas 2.23 times, the CLz of EPI-PBCA-Np was 0.42 times, and theAUC(0-t) of EPI-PBCA-Np was 1.80 times. The rate of protein bindingof EPI was 69.12±5.61%, The rate of protein binding of EPI-PBCA-NPwas 55.21±6.08%.Conclusion: The EPI-PBCA-NP changed the feature ofpharmacokinetics in body of habbits, and prolonged the half life ofEPI, and elevated higher degree of bilogic utilization, and degraded therate of protein binding. |
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