[In vivo comparison of estradiol metabolism in liver microsomes of human, Beagle dog and rat].

The inter-species differences of estradiol metabolism were investigated in human, Beagle dog and rat liver microsomes by comparing enzyme kinetics of parent drug and the formation of its major metabolites. The incubation systems of estradiol with liver microsomes of the three species were optimized in terms of estradiol concentration, microsomal protein content and incubation time. The concentrations of estradiol and its metabolites were measured by LC-MS/MS method. The t1/2, CLint, CLh, Km and Vmax of estradiol incubated with male human liver microsomes were 40.02 +/- 8.32 min, 41.39 +/- 6.57 mL x min(-1) x kg(-1), 13.81 +/- 12.36 mL x min(-1) x kg(-1), 26.8 +/- 6.99 micromol x L(-1) and 0.75 +/- 0.92 micromol x L(-1) x min(-1), respectively. The corresponding parameters of female human were 44.71 +/- 10.21 min, 29.85 +/- 8.97 mL x min(-1) x kg(-1), 0.01 +/- 0.68 mL x min(-1) x kg(-1), 44.2 +/- 7.73 micromol x L(-1) and 1.27 +/- 4.41 micromol x L(-1) x min(-1), that of male dog were 21 +/- 7.33 min, 165.53 +/- 29.33 mL x min(-1) xkg(-1), 26.01 +/- 8.39 mL x min(-1) x kg(-1), 19.5 +/- 7.34 micromol x L(-1) and 1.6 +/- 0.65 micromol x L(-1) x min(-1), that of female dog were 25.5 +/- 5.32 min, 135.11 +/- 42.34 mL x min(-1) x kg(-1), 0.24 +/- 3.18 mL x min(-1) x kg(-1), 8.33 +/- 6.32 micromol x L(-1) and 0.51 +/- 2.15 micromol x L(-1) x min(-1), that of male rat were 5.11 +/- 3.84 min, 485.63 +/- 36.52 mL x min(-1) x kg(-1), 49.57 +/- 15.29 mL x min(-1) x kg(-1), 62 +/- 13.74 micromol x L(-1) and 19.16 +/- 9.67 micromol x L(-1) x min(-1), and that of female rat were 7.0 +/- 3.69 min, 354.82 +/- 33.33 mL x min(-1) x kg(-1), 8.04 +/- 3.23 mL x min(-1) x kg(-1), 35.38 +/- 7.65 micromol x L(-1) and 8.39 +/- 4.91 micromol x L(-1) min(-1), respectively. There were nine metabolites detected from all the three species, but the relative amounts of the metabolites generated were different in three species. The results indicted that the major phase I metabolic pathway of estradiol was similar in the liver microsomes from all the three species. However, the inter-species differences were found in the view of relative amounts of the metabolites as well as the metabolic characteristics of estradiol in liver microsomal incubation.

The application of poly (glycerol-sebacate) as biodegradable drug carrier.

Poly (glycerol-sebacate) (PGS) is an elastomeric biodegradable polymer which possesses the ideal properties of drug carriers. In the present study, we prepared a series of PGS implants (5-FU-PGSs) loaded with different weight percent of 5-fluorouracil (2, 5, 7.5 and 10%). We studied the infrared spectrum properties, in vitro degradation and drug release, in vivo degradation and tissue biocompatibility of 5-FU-PGSs, in order to provide detailed information for the application of PGS as biodegradable drug carrier in cancer therapy. Macroscopically, all 5-FU-PGS wafers in phosphate buffer solution (PBS) kept their geometries during the degradation period of 30 days. The in vitro degradation rates of 5-FU-PGSs were accelerated when higher concentration of 5-FU was doped. Scanning electron microscopy observation showed that the surfaces of 5-FU-PGSs with higher concentration of 5-FU had irregular pits. The cumulative drug release profiles of 5-FU-PGSs exhibited a biphasic release with an initial burst release in the first day. After 7 days, almost 100% cumulative release of 5-FU was found for all 5-FU-PGSs.The degradation rate of 5-FU-PGSs in vivo was much quicker than that in vitro. Hematoxylin and eosin staining showed that no remarkable inflammations were observed in the tissue surrounding 5-FU-PGS implants, suggesting 5-FU-PGSs had good biocompatibility and no tissue toxicity. In vitro anti-tumor activity assay suggested that 5-FU-PGSs exhibited anti-tumor activity through sustained-release drug mode. These results demonstrate that PGS is a candidate of biodegradable drug carriers.