| Medicine Curcuma is the root of a plant of Zingiberaceae and Curcuma genus. Zedoary Turmeric Oil is the medicinal ingredient of Curcuma, with anti-tumor, anti-bacterial, anti-viral, anti-inflammatory and other pharmacological effects. In the past, ZTO is used as injection which is prepared by Tween-80 as solubilizer on clinical applications. It is mainly used for treating the colds caused by viruses, Upper Respiratory Tract Infection or Child Virus Pneumonia. Because of the problems of stability and toxicity, the formulation has been canceled included in Chinese Pharmacopoeia (2010). Although the pharmacological effect of ZTO is clear, the existing formulation of ZTO is too less to meet the needs of clinical medicine. Therefore, it is necessary to develop some new formulations, especially the new oral formulation. This study investigated the pharmacokinetic and tissue distribution of Germacrone which is the components of ZTO after ig administration ZTO-CDP. Besides these, this study explored the security of ZTO-CDP by acute toxicity test for the formulation development of ZTO and effective oral formulations provide the basis for clinical experimental.The study carried out in this paper mainly has the following three aspects:1. Establish the HPLC method to detect the biological samples of Germacrone. The Column was Symmetry C18 (5 ?m,4.6×250 mm). The mobile phase was acetonitrile-water. The eluting sequence was gradient elution:acetonitrile:0?15min 55%?65%; 15?30 min 65%?80%. The column temperature was 25?.The flow rate was 1 ml·min-1. The detection wavelength was 210 nm and the injection volume was 20 ?l. The method is accurate, high precision, stable and has good Reproducibility. The average recovery was more than 80% and the day precision RSD were less than 5%. The Germacrone in the blood plasma, tissue homogenates had a good linear relationship (R2> 0.999) at the concentration range of 23.4-1125 ng/mL.2. Pharmacokinetics and tissue distribution studies of ZTO-CDP. We study the effects of different doses of ZTO-CDP dynamically change characteristics in rats by pharmacokinetic experiments. The results are as follows:The Pharmacokinetics results in rats were accordance with two-compartment model. The average peak of plasma concentration (Cmax) was (330.22±14.88) ng/ml?(183.14±9.73) ng/ml?(99.63±9.52) ng/ml of three doses (1000,500, 200 mg/kg) which is respectively reached the peak at 6.00 h,6.00 h and (5.50±1.00) h after administration. The absorption half-life (t1/2ka) were (6.40±0.89) h, (5.20±1.09) h, (4.80±1.1) h respectively. The distribution half-life (t1/2a) were (2.66±1.10) h, (3.64±0.41) h, (3.63±0.44) h respectively. The elimination half-life (t1/2p) were (5.02±0.38) h, (4.13±0.49) h, (3.89±0.32) h respectively. The area under Concentration-time curve (AUC0-t) were (4139.87±205.71) ng/ml-h, (2340.81±143.25) ng/ml·h, (1056.07±56.16)ng/ml·h. The total elimination rate (CL) were (219.97±16.25) L/h/kg, (185.74±13.83) L/h/kg and (144.20±14.71) L/h/kg respectively.We study the distribution of ZTO-CDP in mice through the organization distribution experiments. The Germacrone had higher distribution in liver and spleen, and has lower in heart and lungs. Besides that the concentration differs little in heart and lung. The distribution order in various tissues were liver> spleen> kidney> lung> heart and the concentration distributed in liver and spleen is much larger than that in heart and lungs.3. The acute toxicity test of ZTO-CDP. The result is as follows:The mice which is fed with the maximum volume (0.4 ml/10g) maximum concentration (0.47 g/ml), after 14 days no death was found in the experimental mice. Mice were sacrificed and dissected after the end of the experiment, no organ abnormalities were found. Also there is no organ pathology in sliced observation which indicates the low toxicity of ZTO-CDP and the possibility of clinical use.The results are as follows:?The results indicated that the HPLC method can be used for the determination of Germacrone, the operation method is simple which can meet the determination of biological samples of Germacrone.?Pharmacokinetics of Germacrone in rats was fitted to two-compartment model. Germacrone could be detected in the blood after 1 h, and tmax was about 6 h. After 24 h, the concentrations of Germacrone in high and middle dose groups were respectively (59.77±11.97) ng/ml and (34.15±6.56) ng/ml, compared with not detecting in low dose group. Cmax and AUC were significantly correlated with the dose. In the study of tissue distribution, Germacrone was significantly higher in the liver and spleen than in other organs, which can be used for the treatment of liver and spleen diseases.?In the acute toxicity test, the dosage of administration equivalent to 77 times of the clinical dose, so we explored the security of ZTO-CDP.Currently, the study about the pharmacokinetic of ZTO rarely reported in literatures. The pharmacokinetic ZTO and it related formulation is not clear. This study investigated the pharmacokinetic and tissue distribution of Germacrone which is the components of ZTO after ig administration ZTO-CDP. Due to ZTO-CDP with good solubility and a lot of repetitive in vivo experiments, the time was limited; this study did not examine its dissolution case. But because of ZTO poor stability, so the related vitro experiments are necessary. We haven't compare it with previous clinical formulations. Relevant experiments remain to be further improved. |
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