The Influence of In Vivo Metabolic Modifications on ADMET Properties of Green Tea Catechins–In Silico Analysis

The health effects of green tea are associated with catechins: (?)-epigallocatechin-3-O-gallate (EGCG), (?)-epigallocatechin, (?)-epicatechin-3-O-gallate, and (?)-epicatechin. An understanding of compound absorption, distribution, metabolism, excretion, and toxicity characteristics is essential for explaining its biological activities. Herein, absorption, distribution, metabolism, excretion, and toxicity properties of in vivo detected metabolites of green tea catechins (GTCs) have been analyzed in silico. The influence of metabolic transformations on absorption, distribution, metabolism, and excretion profiles of GTCs corresponds to the effects of size, charge, and lipophilicity, as already observed for other small molecules. Mutagenic, carcinogenic, or liver toxic effects were predicted only for a few metabolites. Similar to galloylated GTCs EGCG and (--)-epicatechin-3-O-gallate, the sulfo-conjugates were predicted to bind at the warfarin binding site. The low free plasma concentration of these derivatives may be consequential to their serum albumin binding. The activity cliff detected for methylated conjugates of EGCG indicates that GTCs' pro-oxidative activity in bound state comes primarily from free hydroxyl groups of the pyrogallol ring B.     

Chemical delivery systems and soft drugs: Retrometabolic approaches of drug design

Inclusion of metabolic considerations in the drug design process leads to significant development in the field of chemical drug targeting and the design of safer drugs during past few years which is a part of an approach now designated as Retro metabolic drug design (RMDD). This approach represents systematic methodologies that integrate structure–activity and structure–metabolism relationships and are aimed to design safe, locally active compounds with an improved therapeutic index. It embraces two distinct methods, chemical delivery systems and a soft drug approach. Present review recapitulates an impression of RMDD giving reflections on the chemical delivery system and the soft drug approach and provides a variety of examples to embody its concepts. Successful application of such design principles has already been applied to a number of marketed drugs like esmolol; loteprednol etc., and many other candidates like beta blockers, ACE inhibitors, alkylating agents, antimicrobials etc., are also under investigation.     

银杏叶注射液对早期糖尿病肾病尿微量白蛋白的影响

目的:探讨银杏叶注射液对早期糖尿病肾病尿微量白蛋白排泄率的影响。方法:选择早期糖尿病肾病患者84例,随机平均分为2组,对照组给予常规治疗,治疗组在对照组的基础上加用银杏叶注射液10mL,静脉滴注,1次.d-1,连续3wk。比较2组在治疗前后尿微量白蛋白及相关临床、生化指标的变化情况。结果:与对照组比较,治疗组尿微量白蛋白排泄率显著降低(P<0.05)。结论:银杏叶注射液对早期糖尿病肾病具有治疗作用。     

Use of gamma-spectrometry for simultaneous determination of 210Pb, 73As, 109Cd, 203Hg and 59Fe distribution and excretion in rats at low doses

γ-Spectrometry permits the identification and quantification of different γ-isotopes in the same aliquot. To estimate the sensitivity and discriminative power of a comparably small and inexpensive 8% germanium detector, we determined the detection limits for simultaneously applied ²¹⁰Pb, ⁷³As, ¹⁰⁹Cd, ²⁰³Hg and ⁵⁹Fe. The concentration of Fe and of each of the four potential environmental contaminants was determined in aliquots from all organs and tissues 10 days after simultaneous i.v. administration (2 μmol/kg body weight) to adult and growing iron-deficient and iron-adequate rats. Relating these values to the total size of each organ permitted to derive a whole body distribution pattern for all five isotopes in each individual animal. Cumulative renal and faecal excretion values were determined during the 10 day distribution period to calculate the half-lives for both excretory pathways for all five isotopes simultaneously. Distribution and excretion values corresponded well to literature data. Extrapolation of the results showed that the detector would be sensitive enough to discriminate and quantify the five metals at human dietary exposure levels. The results recommend to use γ-spectrometry to investigate kinetic aspects of interactions between toxic and essential trace metals, because the method reduces the number of required animals drastically.     

Urinary and faecal excretion of chrysene and chrysene metabolites by rats after oral,intraperitoneal, intratracheal or intrapulmonary application

The urinary and faecal excretion of chrysene and its phenolic metabolites after oral, intraperitoneal, intratracheal, and intrapulmonary administration to rats have been studied by means of gas chromatography/mass spectrometry. The metabolite profile was found to depend on the mode of excretion and on the route of administration. In all cases the oxidation of chrysene in the 1,2- or 3,4-position predominates, whereas oxidation in the 5,6-position (K-region) seems be a minor pathway.The present study was carried out by the order of the Federal Ministry for Research and Technology (BMFT)     

Trichloroethylene exposure and trichloroethylene metabolites in urine and blood

After trichloroethylene (Tri) inhalation the metabolite trichloroethanol (TCE) is excreted rapidly in the urine, while trichloroacetic acid (TCA) accumulates in the organism due to a high plasma protein binding rate. After exposure of 5 volunteers to 50 ppm Tri for 6 h, 50 g/ml TCA is found in the plasma at the end of the 5th exposure day, the amount of TCE present in the blood amounting to not more than 2.3 g/ml. Instead of the previously used control of TCE + TCA in the urine, it is suggested to determine the metabolites in the blood by means of a gas Chromatographic micro technique which provides a reliable criterion of the preceding Tri exposure.The described study was supported by the Deutsche Forschungsgemeinschaft.     

The Lesch-Nyhan syndrome

Metabolic studies in a case of Lesch-Nyhan syndrome are presented. De novo synthesis of purine was shown to be inhibited upon adenine administration. The excretion of oxypurines is elevated, however, by an increased incorporation of the administered adenine into purine bases. A side effect of adenine administration is the production of the slightly soluble and highly nephrotoxic 2,8-dioxyadenine, which can cause renal damage.     

Tissue distribution and excretion of 125I-lidamycin in mice and rats

AIM: To investigate the tissue distribution, urinary and fecal excretions of 125I-lidamycin (125I-C-1027) in mice and its biliary excretion in rats. METHODS:The total radioactivity assay (RA method) and the radioactivity assay after precipitation with 200 mL/L trichloroacetic add (TCA-RA method) were used to dete-rmine the tissue distribution,and the urinary and fecal excretions of 125I-C-1027 in mice and its biliary excretion in rats. RESULTS:Tissue concentrations reached the peak at the fifth minute after administration of 125I-C-1027 to mice. The highest concentration was in kidney, and the lowest in brain at all test-time points. The organs of the concentrations of 125I-C-1027 from high to low were kidney, lung, liver, stomach, spleen, uterus, ovary, intestine, muscle, heart, testis, fat, and brain in mice. The accumulative excretion amounts of 0-24 h, and 0-96 h after administration of 125I-C-1027 were 68.36 and 71.64% in urine, and 2.60 and 3.21% in feces of mice, respectively, and the accumulative excretion amount of 0-24 h was 3.57% in bile in rats. CONCLUSION: Our results reflect the characteristics of the tissue distribution, urinary and fecal excretions of 125I-C-1027 in mice and the biliary excretion of 125I-C-1027 and its metabolites in rats, and indicate that 125I-C-1027 and its metabolites are mainly distributed in kidney, and excreted in urine.     

二巯丙磺钠对毒鼠强在家兔体内排泄的影响

目的 研究二巯丙磺钠(Na-DMPS)对动物体内毒鼠强排泄的影响。方法 应用气相色谱—氮磷检测器法测定染毒家兔的毒鼠强血浆浓度和尿液含量,并进行代谢动力学分析。结果 Na-DMPS没有降低中毒动物血液中毒鼠强浓度,对各代谢动力学参数没有明显影响,亦未增加中毒动物24h尿中毒鼠强含量。结论 Na-DMPS不能加快毒鼠强从动物体内的排泄。