Genistein, one of the most active natural flavonoids, exerts various biological effects including chemoprevention, antioxidation, antiproliferation and anticancer. More than 30 clinical trials of genistein with various disease indications have been conducted to evaluate its clinical efficacy. Based on many animals and human pharmacokinetic studies, it is well known that the most challenge issue for developing genistein as a chemoprevention agent is the low oral bioavailability, which may be the major reason relating to its ambiguous therapeutic effects and large interindividual variations in clinical trials. In order to better correlate pharmacokinetic to pharmacodynamics results in animals and clinical studies, an in-depth understanding of pharmacokinetic behavior of genistein and its ADME properties are needed. Numerous in vitro/in vivo ADME studies had been conducted to reveal the main factors contributing to the low oral bioavailability of genistein. Therefore, this review focuses on summarizing the most recent progress on mechanistic studies of genistein ADME and provides a systemic view of these processes to explain genistein pharmacokinetic behaviors in vivo. The better understanding of genistein ADME property may lead to development of proper strategy to improve genistein oral bioavailability via mechanism-based approaches.

ABSTRACT:It was recently proposed that the improved oral bioavailability of genistein aglycone and conjugates in Bcrp1(؊/؊) mice is mainly due to increased intestinal absorption of aglycone and subsequent elevated exposure to conjugation enzymes. Here we tested this proposed mechanism and found that intestinal absorption of genistein aglycone did not increase in Bcrp1(؊/؊) mice compared with wild-type mice using an in situ mouse intestinal perfusion model and that inhibition of breast cancer resistance protein (BCRP) in Caco-2 cells also did not significantly increase permeability or intracellular concentration of aglycone. Separately, we showed that 5-to 10-fold increases in exposures of conjugates and somewhat lower fold increases (<2-fold) in exposures of aglycone were apparent after both oral and intraperitoneal administration in Bcrp1(؊/؊) mice. In contrast, the intestinal and biliary excretion of genistein conjugates significantly decreased in Bcrp1(؊/؊) mice without corresponding changes in aglycone excretion. Likewise, inhibition of BCRP functions in Caco-2 cells altered polarized excretion of genistein conjugates by increasing their basolateral excretion. We further found that genistein glucuronides could be hydrolyzed back to genistein, whereas sulfates were stable in blood. Because genistein glucuronidation rates were 110% (liver) and 50% (colon) higher and genistein sulfation rates were 40% (liver) and 42% (colon) lower in Bcrp1(؊/؊) mice, the changes in genistein exposures are not mainly due to changes in enzyme activities. In conclusion, improved bioavailability of genistein and increased plasma area under the curve of its conjugates in Bcrp1(؊/؊) mice is due to altered distribution of genistein conjugates to the systemic circulation.

In multi-cast scenario, all desired users are divided into K groups. Each group receives its own individual confidential message stream. Eavesdropper group aims to intercept K confidential-message streams. To achieve a secure transmission, two secure schemes are proposed: maximum group receive power plus null-space (NS) projection (Max-GRP plus NSP) and leakage. The former obtains its precoding vector per group by maximizing its own group receive power subject to the orthogonal constraint, and its AN projection matrix consist of all bases of NS of all desired steering vectors from all groups. The latter attains its desired precoding vector per group by driving the current confidential message power to its group steering space and reducing its power leakage to eavesdropper group and other K − 1 desired ones by maximizing signal to leakage and noise ratio (Max-SLNR). And its AN projection matrix is designed by forcing AN power into the eavesdropper steering space by viewing AN as a useful signal for eavesdropper group and maximizing AN to leakage-and-noise ratio (Max-ANLNR). Simulation results show that the proposed two methods are better than conventional method in terms of both bit-error-rate (BER) and secrecy sum-rate per group. Also, the leakage scheme performs better than Max-GRP-NSP , especially in the presence of direction measurement errors. However, the latter requires no channel statistical parameters and thus is simpler compared to the former.

Abstract. The low bioavailability of genistein has impeded its development into a therapeutic agent. Our earlier studies indicate that glucuronidation is one of the major barriers to genistein oral bioavailability. This study will determine how sulfotransferases and efflux transporters affect its intestinal disposition. A rodent intestinal perfusion model and S9 fractions were used. Sulfate excretion rates were comparable to glucuronide excretion in mouse small intestine but significantly higher than glucuronide excretion in mouse colon, which is different from rat intestinal disposition but similar to disposition in Caco-2 cells. To define efflux transporter(s) involved in sulfate excretion, two organic anion inhibitors (estrone sulfate and dihydroepiandrosterone sulfate) or a multidrug resistance protein inhibitor (MK-571) were used but neither was able to decrease the excretion of genistein sulfates. In contrast, the excretion of genistein sulfate decreased substantially (>90%) in small intestine of breast cancer resistance protein (BCRP) knockout mice and became undetectable in colon of the knockout mice. The excretion rates of genistein glucuronide in the small intestine of BCRP knockout mice were also significant decreased (78%). This study shows clearly that BCRP facilitates the cellular genistein sulfate excretion by removing sulfates to prevent their backward hydrolysis and to limit substrate inhibition, indicating that BCRP plays a dominant role in genistein sulfate excretion and a significant role in genistein glucuronide excretion in the mouse intestine.

Molecular dynamics has been employed to simulate the well-known high energy density compound epsilon-CL-20 (hexanitrohexaazaisowurtzitane) crystal and 12 epsilon-CL-20-based PBXs (polymer bonded explosives) with four kinds of typical fluorine polymers, i.e., polyvinylidenedifluoride, polychlorotrifluoroethylene, fluorine rubber (F(2311)), and fluorine resin (F(2314)) individually. The elastic coefficients, isotropic mechanical properties (tensile moduli, bulk moduli, shear moduli, and poission's ratios), and bonding energy are first reported for epsilon-CL-20 crystal and epsilon-CL-20-based polymer bonded explosives (PBXs). The mechanical properties of epsilon-CL-20 can be effectively improved by blending with a small amount of fluorine polymers, and the whole effect of the adding fluorine polymers to improve mechanical properties of PBXs along the three crystalline surfaces of epsilon-CL-20 is found to be (100) approximately (001) > (010). The interaction between each of the crystalline surfaces and each of the fluorine polymers is different, and the ordering of binding energy for the three surfaces is (001) > (100) > (010); F(2314) always has the strongest binding ability with the three different surfaces. F(2314) can best improve the ductibility and tenacity of PBX when it is positioned on epsilon-CL-20 (001) crystal surface. The calculations on detonation performances for pure epsilon-CL-20 crystal and the four epsilon-CL-20-based PBXs show that adding a small amount of fluorine polymer into pure epsilon-CL-20 will lower detonation performance, but each detonation parameter of the obtained PBXs is still excellent.