Study on tissue distribution of HRZ coating material of sustained-release anti-tuberculosis drug in rabbit spinal tuberculosis model

English Keywords:Spinal tuberculosis  Drug release  Tissue distribution  Isoniazid  Rifampicin  Pyrazinamide

English Abstract:

  【Abstract】 Objectives: To observe the drug release and tissue distribution characteristics of anti-tuberculosis drug′s sustained-release coating in rabbit spinal tuberculosis model. Methods: New Zealand white rabbits of either sex weighing 3.00±0.25kg were selected. A total of 120 spinal tuberculosis models were constructed and screened by vertebral body drilling and infusion of Mycobacterium tuberculosis. According to different drug delivery dosage forms and ways of the "isoniazid (INH, H), rifampicin (RFP, R), and pyrazinamide (PZA, Z)", the rabbit model of spinal tuberculosis were randomly divided into four groups of 30 rabitts: group A, sustained-releasematerial group, with local implantation of sustained-release of HRZ material (300mg/kg)+ autogenous iliac bone; group B, local administration group, with local implantation of HRZ drug crystals (H,12.5mg/kg; R, 12.5mg/kg; Z, 25.0mg/kg); group C, intragastrically fed group, fed intragastricallyat fixed time daily (H, 12.5mg/kg/d; R, 12.5mg/kg/d; Z, 25.0mg/kg/d); group D, sham operation perfusion group, with daily fixed time perfusion (dose: H, 12.5mg/kg/d; R, 12.5mg/kg/d; Z, 25.0mg/kg/d). All groups were given the same dose in a single dose. Group A and B were given single dose, while group C and D were given multiple doses consecutively. Five rabbits were randomly selected from each group at each time point, and drug concentrations of H, R and Z in venous blood, psoas major muscle and bone tissue of each group were determined by high performance liquid chromatography after administration(7d, 14d, 28d and 84d). Drug concentration-time curves were drawn to observe drug release properties and tissue distribution characteristics. Results: The single dose of the four groups was the same, and the total dose of HRZ in groups A and B was significantly lower than that in groups C and D(P<0.01). The drug concentrations of H, R and Z in psoas major muscle and bone tissue in group A were significantly higher than those in groups C and D(P<0.01). In group A, the concentrations of H, R and Z in venous blood were very low orundetected(P>0.05). In group A, the drug-time curve in psoas major muscle and bone tissue was smooth without sudden release. In group A, the concentration of H(14.22±1.07μg/ml), R(12.66±1.12μg/ml), and Z(28.93±1.30μg/ml) in psoas major muscle and bone tissue H(12.46±0.29μg/ml), R(10.34±0.32μg/ml), and Z(26.21±0.82μg/ml) reached the highest on the 7th day after administration, and the lowest on the 84th day after administration. At this time, the concentrations of H(6.69±1.42μg/ml), R(6.28±0.77μg/ml), and Z(19.88±0.90μg/ml) in the bone tissue of the lesion were more than 10 times of the minimum inhibitory concentration(MIC) at each detection time point. The drug concentrations in the psoas major muscle of H(8.19±1.98μg/ml), R(16.87±3.03μg/ml), and Z(91.18±11.12μg/ml) and bone tissue of H(5.70±1.25μg/ml), R(13.06±1.26μg/ml), and Z(79.00±8.68μg/ml) in group B were higher at 7d after surgery, and decreased sharply, which were undetectable in both psoas major muscle and bone tissue 28d after surgery. In group B, the concentration of drugs(H, R, and Z) in venous blood was very low or could not be detected. The concentration of drugs(H, R, and Z) in venous blood, psoas major muscle and bone tissue of C and D groups could be measured at each detection time point.The concentrations of drugs (H, R, and Z) in bone tissue of groups C and D were maintained at relatively stable and low levels. Conclusions: The sustained-release HRZ material has satisfactory local drug release performance in rabbit spinal tuberculosis lesions, and the tissue distribution characteristics are high local drug concentration and low peripheral drug concentration.