Absorption and distribution of rokitamycin in beagle dogs

Tissue distribution of rokitamycin (TMS-19-Q) was studied after oral administration of 50 mg/kg to fasted Beagle dogs. Tissue concentrations of TMS-19-Q reached their peaks at 1-2 hours after the administration. The order of tissue concentrations of TMS-19-Q was liver greater than kidney greater than spleen greater than lung greater than mesenteric lymph node greater than heart greater than tonsil greater than serum greater than prostate gland greater than uterus greater than skin. At the peak time, drug concentrations in tonsil and lung were about 1.1 and 1.4 times higher, respectively, than that in serum.     

Comparative tissue distribution and excretion of [1-14C]acrylamide in beagle dogs and miniature pigs

Male beagle dogs and miniature pigs were given acrylamide in the diet for 3-4 wk at a dosage of 1 mg/kg/day. They were then given [1-14C]acrylamide as a single oral dose of 1 mg/kg. The animals were killed 6 hr or 1, 2, 4 or 14 days after administration of the radioactive compound and tissues were analysed for radioactivity. The radiolabelled material was distributed to a major extent in muscle tissue in both species (31-35% of the dose at 6 hr and 5-7% at 14 days). Although the nervous system is the primary target for acrylamide monomer toxicity, less than 1% of the administered 14C was found in the brain in both species. No neurotoxic signs were evident during the exposure period at the dosage used. Analysis of discrete areas of the brain for radioactivity revealed that the levels of penetration of [1-14C]acrylamide in brain paralleled the vascularization pattern of the tissues. Approximately 60% of the administered radiolabel was excreted in the urine in both species and smaller amounts were excreted in the faeces. However, recovery in the faeces was higher in pigs (c. 25%) than in dogs (c. 7%) and this and the considerably higher levels demonstrated in the gastro-intestinal tract of the pigs indicated that the absorption of acrylamide was more rapid and more extensive in dogs than in pigs.     

Quantitative analysis of (-)-epigallocatechin gallate in tea leaves by high-performance liquid chromatography]

The quantitative analysis of (-)-epigallocatechin gallate (EGCG) in tea (Camellia sinensis L.) was performed by high-performance liquid chromatography (HPLC) with a C-18 reversed-phase column. EGCG was then eluted within 20 min by using methanol-water-acetic acid (20:75:5 (v/v/v)) as an eluent. As an internal standard, tryptophan was used. The content of EGCG in five kinds of green tea (sencha, gyokuro, bancha, matsucha and oolong tea) and in a cup of those was determined by both the extraction method with 50% (v/v) methanol and the infusion method with water. The largest amount of EGCG was obtained from matsucha by the extraction method, or from sencha by the infusion method. Furthermore, EGCG contents in various parts of the tea plant were examined. The first leaf had the highest concentration of EGCG, and the concentration of EGCG decreased with the aging of the leaf.     

表没食子儿茶素没食子酸酯抗肿瘤作用机制的研究进展

绿茶中的活性成分已经被证明具有预防和控制癌症的作用,其中表没食子儿茶素没食子酸酯（EGCG）抗癌活性最高。EGCG能够通过调控氧化应激、阻滞肿瘤细胞周期、抑制肿瘤血管形成、诱导肿瘤细胞凋亡等途径实现抗肿瘤效果。因此对EGCG抗肿瘤作用机制的进行了综述,以期为EGCG的临床应用提供参考。     

Generation of mouse monoclonal antibody against (-)-epigallocatechin gallate

Green tea is an acknowledged cancer preventive in Japan, and the main constituent of green tea catechins is (-)-epigallocatechin gallate (EGCG). To investigate the bioavailability of EGCG in humans, we generated a monoclonal antibody against EGCG in BALB/c mice by immunizing thyroglobulin-conjugated EGCG. Out of 32 hybridoma cell lines, three hybridomas were selected by enzyme-linked immunosorbent assay (ELISA), and then determined by surface plasmon resonance assay: One hybridoma TG38 produced a specific monoclonal antibody against EGCG. The primary structure of TG38 light chain was then deduced from DNA sequence of the light chain gene. The NCBI-BLAST search showed the uniqueness of TG38 monoclonal antibody, and three amino acid residues specific for TG38 were aligned on two loops and one beta-sheet of the tertiary structure of the antibody. The TG38 antibody is the first monoclonal antibody against EGCG and catechins, since it bound to four green tea catechins with a galloyl group.     

Absorption,distribution, metabolism and excretion of the novel SARM GTx-024 [(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide] in rats

Abstract

1. GTx-024, a novel selective androgen receptor modulator, is currently being investigated as an oral treatment for muscle wasting disorders associated with cancer and other chronic conditions.

2. Absorption of GTx-024 was rapid and complete, with high oral bioavailability. A wide tissue distribution of [¹⁴C]GTx-024 derived radioactivity was observed. [¹⁴C]GTx-024-derived radioactivity had a moderate plasma clearance (117.7 and 74.5?mL/h/kg) and mean elimination half-life of 0.6?h and 16.4?h in male and female rats, respectively.

3. Fecal excretion was the predominant route of elimination, with ～70% of total radioactivity recovered in feces and 21–25% in urine within 48?h. Feces of intact rats contained primarily unchanged [¹⁴C]GTx-024 (49.3–64.6%). Metabolites were identified in urine and feces resulting from oxidation of the cyanophenol ring (M8, 17.6%), hydrolysis and/or further conjugation of the amide moiety (M3, 8–12%) and the cyanophenol ring (M4, 1.3–1.5%), and glucuronidation of [¹⁴C]GTx-024 at the tertiary alcohol (M6, 3.5–3.7%). There was no quantifiable metabolite in plasma.

4. In summary, in the rat GTx-024 is completely absorbed, widely distributed, biotransformed through several metabolic pathways, and eliminated in feces primarily as an unchanged drug.     

Disposition and metabolism of sodium 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl]-gamma -oxobenzenebutanoate in rats and dogs

The disposition of sodium 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl]-gamma-o xo benzenebutanoate (L-648,051) was determined in rats and dogs. L-648,051 is a potent receptor antagonist for leukotriene D4 and is potentially useful in the treatment of asthma and other allergic disorders. After a dosage of 10 mg/kg iv, L-648,051 declined rapidly with a half-life of approximately 2 min in rat and dog plasma. Although the compound was well absorbed, it exhibited poor bioavailability due to efficient first-pass metabolism. In rats receiving 25, 50, and 150 mg/kg po, bioavailabilities were 0.5, 4.8, and 38.7%, respectively. In dogs, bioavailability of 10 and 50 mg/kg po was 0 and 23%, respectively. Two metabolites were identified, 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl-gamma- hydroxybenzenebutanoic acid (metabolite I), formed by ketoreduction, and 4-[(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl)sulfonyl] benzeneacetic acid (metabolite II) formed by catabolic oxidation of the butanoic acid moiety of L-648,051. Ketoreduction resulted in the production of a chiral center and two enantiomers of metabolite I. In vitro studies suggest that rat erythrocytes formed the (+)-enantiomer exclusively. When L-648,051 was administered orally or iv to rats, both the (+)- and (-)-enantiomers were observed in the plasma. The data suggest that either two L-648,051 ketoreductases were present or that inversion of the hydroxyl stereocenter of metabolite I occurred.     

Absorption, distribution, and retention of inhaled selenious acid and selenium metal aerosols in beagle dogs

We studied the distribution and retention of inhaled selenious acid and selenium metal aerosols which were similar in size and chemical form to selenium aerosols that may be produced during fossil fuel combustion. Beagle dogs were given 10 to 61 micrograms Se/kg of body weight by inhalation. Aerosols generated for the inhalation exposures were also collected and instilled into the upper respiratory tracts or stomachs of additional dogs to measure systemic absorption at these sites. Selenium-75, incorporated into the aerosols, was used to determine the Se content in the whole animal, excreta, and individual tissues as a function of time. Virtually all of the inhaled selenious acid aerosol was rapidly absorbed into the blood from the lungs, gastrointestinal tract, and the nasal membranes. Selenium metal aerosols were less rapidly absorbed. Selenium that was absorbed into the blood was translocated to the liver, kidney, spleen, and heart. Selenium-75 in these organs had a biological half-life of 30 to 40 days. Approximately 50% of the deposited Se was eliminated with a biological T1/2 of 1.2 days. Urine was the major route of excretion, accounting for 70 to 80% of the excreted Se. The long-term component of the whole-body retention function for both inhaled aerosols had a half-life of about 34 days and accounted for about 20% of the initial Se dose. The data suggested that although absorption of selenious acid into blood following inhalation was more rapid than absorption of selenium metal, once absorbed the disposition of both compounds was similar.     

Synthesis of 2-deoxy-2-[(2,2-difluoro-3-hydroxytetradecanoyl)amino]-3-O- [(R)-3-(tetradecanoyloxy)tetradecanoyl]-D-glucopyranose 4-phosphate

2-Deoxy-2-[(2,2-difluoro-3-hydroxytetradecanoyl)amino]-3-O-[(R)-3- (tetradecanoyloxy)tetradecanoyl]-D-glucopyranose 4-phosphates (9H,L) were synthesized from allyl 2-amino-2-deoxy-4,6-O- isopropylidene-beta-D-glucopyranoside (1), (+/-)-3-[(benzyloxycarbonyl)oxy]-2,2-difluorotetradecanoic acid, and (R)-3- (tetradecanoyloxy)tetradecanoic acid. Both compounds 9H and 9L were more active than GLA-60 for the prostaglandin D2 releasing test on macrophages.     

Comparative examination of anti-proliferative activities of (-)-epigallocatechin gallate and (--)-epigallocatechin against HCT116 colorectal carcinoma cells

We compared anti-proliferative activities of (-)-epigallocatechin gallate (EGCG) and (-)-epigallocatechin (EGC) against HCT116 colorectal carcinoma cells. These catechins inhibited cell growth to nearly the same extent at low cell confluency in plates. However, their inhibitory effect grew weaker as cell confluence increased, and this tendency was more conspicuous for EGC than for EGCG. Both EGCG and EGC activated the phosphorylation of the major MAPKs, ERK, JNK, and p38, in the HCT116 cells as in many other established human cancer cells though to different extents. Cell cycle analyses, DNA fragmentation assays, and TUNEL assays as well as Western blot assays suggested that these catechins inhibited cell growth through mitogen-activated protein kinase (MAPK)-mediated apoptosis rather than cell cycle regulation.     

Effects of (-)-epigallocatechin gallate on the development of morphine-induced physical dependence

Among the various nervous systems and signaling components involved in the development of morphine withdrawal symptoms, sensitization of the brain dopaminergic nervous system and an increase in the cAMP levels in the locus coeruleus are believed to be the most important cellular events. This study tested the effects of (-)-epigallocatechin gallate (EGCG), a major compound of green tea, on the development of morphine-induced withdrawal symptoms. All the naloxone-precipitated withdrawal symptoms in morphine-dependent animals were inhibited by an EGCG pretreatment in a dose-dependent manner, being forepaw tremor, rearing, teeth chattering, urination, and wet dog shake were more sensitive than jumping and ptosis. In addition, EGCG showed moderate inhibitory effects on the morphine-induced increase in the cAMP levels in the locus coeruleus at 100 mg/kg and the signaling of the dopamine D2 receptor at 100 microM. Effects of EGCG on the sequestration of D2 receptor were inconclusive. These results suggest that EGCG has strong pharmacological activity against the development of morphine dependence, which can be partly explained by its inhibitory effects on the morphine-induced increase in the cAMP levels in the locus coeruleus and the signaling of the dopamine D2 receptor.     

New method for the synthesis of methyl-4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate

A new simple method involving a reduced number of steps is proposed for the synthesis of methyl-4-[(3, 4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl]-4-piperazinecarboxylate (GR-89696), which is an agonist of κ-opioid receptors (K_d = 0.41 nM). Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 43, No. 2, pp. 48–50, February, 2009.     

Antioxidant chemistry of green tea catechins. New oxidation products of (-)-epigallocatechin gallate and (-)-epigallocatechin from their reactions with peroxyl radicals

The green tea catechins (-)-epigallocatechin gallate (EGCG) and (-)-epigallocatechin (EGC) react with peroxyl radicals generated by thermolysis of the azo initiator 2,2'-azobis(2, 4-dimethylvaleronitrile) (AMVN) to produce several oxidation products. Structure elucidation of these products can provide insights into specific mechanisms of antioxidant reactions. We isolated and identified a previously unreported reaction product of EGCG and three reaction products of EGC. In the EGCG product, the B-ring was transformed into a ring-opened unsaturated dicarboxylic acid moiety. The EGC products include a seven-membered B-ring anhydride and a symmetrical EGC dimer, both analogues of previously described EGCG oxidation products. The third EGC product was an unsymmetrical dimer. In all identified products, changes occurred solely in the B-ring of EGCG or EGC. This confirmed our previous observation that the principal site of antioxidant reactions in EGCG and EGC is the trihydroxyphenyl B-ring, regardless of the presence of a 3-galloyl moiety. A stoichiometric factor n of 4.16 +/- 0.51 was measured for EGCG, whereas factors of 2.20 +/- 0.26 was found for EGC and 2.33 +/- 0.18 measured for methyl gallate. These values represent the net peroxyl radical trapping per catechin molecule by several competing reactions. EGCG and EGC oxidation involves addition of oxygen, which is not derived from water, but most likely from atmospheric oxygen via peroxyl radicals. Characteristic oxidation products may be useful markers for antioxidant actions in living systems.     

Synthesis and Antiproliferative Activity of 3-[(R-Hydrazono)Methyl]Cyclobutane-1,1,2,2-Tetracarbonitriles and 3-[(2-R-Hydrazono)Methyl]-6-Methylcyclohex-4-Ene-1,1,2,2-Tetracarbonitriles

Pharmaceutical Chemistry Journal - Aseries of cyclobutane-1,1,2,2-tetracarbonitriles contained a compound with significant activity against various cancer cell lines. The compound featured a...     

Improved synthesis of an ester-type prodrug, 1-acetoxyethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-1- propenyl]-3-cephem-4-carboxylate (BMY-28271)

1-Acetoxyethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3- [(Z)-1-propenyl]-3-cephem-4-carboxylate (BMY-28271) is an ester-type prodrug of cephalosporin for oral use. Methods suitable for large scale preparation were investigated. The yield was improved by esterification of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido]cep hem-4-carboxylic acid (11) followed by removal of the trityl group and, in addition, column chromatographic purification at each step was eliminated by optimization of the reaction conditions.     

Bioavailability of 5-[4-(1-methylcyclohexylmethoxy)benzyl]-thiazolidine-2,4-dione ( ADD-3878) in beagle dogs

The fundamental pharmacokinetic properties of ADD-3878 were evaluated and the bioavailability of the drug after oral administration was determined in beagle dogs.A pharmacokinetic analysis after intravenous injection of the drug revealed biphasic elimination of the plasma ADD-3878 concentration following a biexponential model with a t_{$\text{1}\text{2}$,α} of 0.27 h and a t_{$\text{1}\text{2}$,β} of 17.11 h. The gastrointestinal absorption of ADD-3878 in solution was significantly faster than those in suspensions. The particle size of ADD-3878 crystals affected both the extent and rate of bioavailability. Furthermore, a significant effect of food on the bioavailability of the drug was observed; the absorption in tablets after food ingestion was approximately double of that in the fasting state. The maximum plasma levels and the areas under the curve at various doses of tablets were proportional to the doses. In a multiple-dose study, there was no unusual accumulation of plasma ADD-3878 concentration.     

Tissue distribution of cefminox in beagle dogs

A new cephamycin antibiotic, cefminox (MT-141, CMNX), was intravenously infused into Beagle dogs at a dose of 40 mg/kg in order to study it's distribution to various tissues. The following results were obtained. The maximum serum concentration of CMNX observed at the end of the infusion period was 102.3 micrograms/ml, and then the concentration decreased. The biological half-life of CMNX in serum was 37.0 minutes. This half-life was similar to the results of previous studies with Beagle dogs and rabbits. The maximum concentrations in tissues and body fluids were highest in B-bile followed by kidney, urinary bladder, serum, liver, vagina, uterus, pericardiac fluid, trachea, ovary, lung, gallbladder, parotid gland, heart, tonsil, thymus, spleen, pancreas, aqueous humor and cerebrospinal fluid, in that order and not detected in brain. The maximum concentrations in gallbladder, B-bile, pericardiac fluid and cerebrospinal fluid were found at 1-2 hours after administration. In other tissues and body fluids, they were obtained at the end of the infusion period. The area under the tissue concentration curve (AUC) was highest in the urinary bladder followed by the kidney, vagina, liver, uterus, gallbladder, trachea, ovary and lung, in that order. These results suggest that CMNX is useful for various infectious diseases in these tissues. The pharmacokinetic parameter (K1i/K2i) derived from serum and tissue concentrations using the deconvolution method well correlated to maximum tissue concentrations.