| 2-methoxyestradiol is the natural metabolites of estrogen which is discoveried in the body in the 70 years of the 20th century. Recently, it is found that 2-ME have a board-spectrum anti-tumor effect and it can inhibit the growth and metastasis of tumor according to the deeply study at home and abroad. There are some reports in the literature saying that.2-methoxyestradiol have a fast elimination and there are lack of correlation between the drug concentration in plasma to the oral dose, but, no one has specifically studied about what have caused these reasons. This study is to find these reasons through a series of research, such as the metabolism in the animal tissue, and the gastrointestinal absorption in situ, et al, to prove that 2-ME is or not can be designed for oral administration.There are four parts about this article, such as the study of the metabolism in the animal tissue, the study of the gastrointestinal absorption in situ, the study of the oral formulation and the bioavailability and the tissue distribution.Fist, we used the method of incubation in vitro to study the metabolism of 2-ME in some different bomogenate of mouse tissues. We found that liver is the main metabolism tissue of 2-ME, and the metabolism in the other tissues is rare. In the administration of the concentration of 152μg·ml-1 (drug quality/volume of the homogenate), the metabolism percentage of different parts are:liver 12.1±2.2%, kidney 4.7±1.07%, lung 3.9±1.04%, spleen 3.2±1.8%, gastric 2.3±0.33%, smallintestine 1.7±0.47%, colon 1.1±0.45%, heart 0.9±0.75%. Then we studied the metabolism about the low, medium and high concentrations were 6.0876μg·ml-1, 40.584μg·ml-1 and 152μg·ml-1 of 2-ME in the bomogenate of liver. According to this study we found that the metabolism of 2-ME become into non-linear from linear with the increasing of the concentration of 2-ME Then we draw the metabolic curve, and calculate the metabolic parameters, and the metabolism were:Km=15.23μg·ml-1, Vm=2.186μg·ml-1·h-1. According to this study we can have a conclusion that there is maybe first pass effect about 2-ME in vivo.Second, we used the model of gastrointestinal absorption of rats in vivo to study the absorption of 2-ME in the rats' stomach, different segments of small intestine and colon. At a low concentration (the concentration of intestinal fluid is 10.146μg·ml-1), gastric and intestinal have a favorable absorption to 2-ME, and the absorption rate is over 80% in 4h. But, with the concentration of 2-ME increasing to 50.73μg·ml-1 and 507.3μg·ml-1, the absorption rate decreased significantly in the stomach and intestinal. According to this study we found that when the concentration of the 2-ME increased to a certain degree, there is a saturation process to the absorption of 2-ME in the body, thus inhibiting the full absorption of 2-ME.Then we prepared the capsule of 2-ME. The accumulate quantity of the release of the formulation compared to the crude drug of 2-ME, increased to 79.7±0.13% from 49.08±0.04% in 45 min.Next, we studied the bioavailability and the tissue distribution of the oral formulation. The result is that the bioavailability is very low whether low-dose or high-dose, they are all not to 1%, and the bioavailability of low-dose is higher than that of high-dose. The drug of 2-ME is mainly transport to the liver after oral administration, which is accounting for more than 90%.At last, we had a analysis of the in vitro release and the in vivo absorption, the results is that the release in vitro and the absorption in vivo are relevant well at low concentration, but, they are relevant bad at high concentration.According to the above descriptions, we know that the absorption irregular of 2-ME oral administration is not because the problems of the formulation, but that is because there is a saturated process after oral administration, which will inhibit the fully absorption to the drug. At the same time, there is obvious first pass effect of liver.
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