Absorption, metabolism, and excretion of [14C]evogliptin tartrate in male rats and dogs.

The objective of this study was to determine the absorption, excretion, and metabolism of a novel, oral antihyperglycemic drug, evogliptin, in male rats and dogs. Plasma, urine, feces, and expired air samples were collected after a single oral dose administration of [14C]evogliptin, samples were analyzed by measuring overall radioactivity levels using high-performance liquid chromatography (HPLC), and radioactivity levels were measured by utilizing LC-tandem mass spectrometry (LC-MS/MS). The total amounts of radioactivity excreted in urine, feces, and expired air up to 168 h after administration of [14C]evogliptin tartrate to rats (30 mg evogliptin/kg) and dogs (10 mg evogliptin/kg) were 96.7% and 96.8% of initial doses administered, respectively. The extent of urinary and fecal excretion in the rat up to 168 h constituted 29.7% and 66.5% of the given dose, respectively; and in dog was 43.3% and 53.5%, respectively. A total of 23 possible metabolites were detected with radiochromatograms of plasma, urinary, and fecal samples, but only the structures of 12 metabolites were identified via LC-MS/MS analysis. Evogliptin was the major component. Regarding the total radiochromatographic peak areas, peaks 9 (evogliptin acid) and 11 (hydroxyevogliptin) were the major metabolites in rats, and peaks 8 [4(S)-hydroxyevogliptin glucuronide], 15 [4(S)-hydroxyevogliptin], and 17 [4(R)-hydroxyevogliptin] were the predominant metabolites in dogs. Data demonstrated that evogliptin was the major component excreted in urine and feces of rats and dogs, but the metabolite profiles varied between species.

Cyclopamine tartrate, an inhibitor of Hedgehog signaling, strongly interferes with mitochondrial function and suppresses aerobic respiration in lung cancer cells.

BACKGROUND: Aberrant Hedgehog (Hh) signaling is associated with the development of many cancers including prostate cancer, gastrointestinal cancer, lung cancer, pancreatic cancer, ovarian cancer, and basal cell carcinoma. The Hh signaling pathway has been one of the most intensely investigated targets for cancer therapy, and a number of compounds inhibiting Hh signaling are being tested clinically for treating many cancers. Lung cancer causes more deaths than the next three most common cancers (colon, breast, and prostate) combined. Cyclopamine was the first compound found to inhibit Hh signaling and has been invaluable for understanding the function of Hh signaling in development and cancer. To find novel strategies for combating lung cancer, we decided to characterize the effect of cyclopamine tartrate (CycT), an improved analogue of cyclopamine, on lung cancer cells and its mechanism of action. METHODS: The effect of CycT on oxygen consumption and proliferation of non-small-cell lung cancer (NSCLC) cell lines was quantified by using an Oxygraph system and live cell counting, respectively. Apoptosis was detected by using Annexin V and Propidium Iodide staining. CycT's impact on ROS generation, mitochondrial membrane potential, and mitochondrial morphology in NSCLC cells was monitored by using fluorometry and fluorescent microscopy. Western blotting and fluorescent microscopy were used to detect the levels and localization of Hh signaling targets, mitochondrial fission protein Drp1, and heme-related proteins in various NSCLC cells. RESULTS: Our findings identified a novel function of CycT, as well as another Hh inhibitor SANT1, to disrupt mitochondrial function and aerobic respiration. Our results showed that CycT, like glutamine depletion, caused a substantial decrease in oxygen consumption in a number of NSCLC cell lines, suppressed NSCLC cell proliferation, and induced apoptosis. Further, we found that CycT increased ROS generation, mitochondrial membrane hyperpolarization, and mitochondrial fragmentation, thereby disrupting mitochondrial function in NSCLC cells. CONCLUSIONS: Together, our work demonstrates that CycT, and likely other Hh signaling inhibitors, can interrupt NSCLC cell function by promoting mitochondrial fission and fragmentation, mitochondrial membrane hyperpolarization, and ROS generation, thereby diminishing mitochondrial respiration, suppressing cell proliferation, and causing apoptosis. Our work provides novel mechanistic insights into the action of Hh inhibitors in cancer cells.

Dual-directional regulation of drug permeating amount by combining the technique of ion-pair complexation with chemical enhancers for the synchronous permeation of indapamide and bisoprolol in their compound patch through rabbit skin.

To achieve the synchronous skin permeation of indapamide (IND) and bisoprolol (BSP) in their compound patch, the techniques of ion-pair complexation and chemical enhancers were combined to dual-directionally regulate drug permeating amounts. Ion-pair complexes of BSP and various organic acids were formed by the technique of ion-pair complexation. Among the complexes formed, bisoprolol tartrate (BSP.T) down-regulated the permeating amount of BSP to the same extent as that of IND. Then, to simultaneously up-regulate the amounts of the two drugs, an enhancer combination of 15.8% Span80 (SP), 6.0% Azone (AZ) and 2.2% N-methyl pyrrolidone (NMP) was obtained by central composite design and exhibited an outstanding and simultaneous enhancement on IND and BSP with enhancing ratio (ER) of 4.52 and 3.49, respectively. The effect of the dual-directional regulation was evaluated by in vitro permeation experiments and in vivo pharmacokinetic studies. For IND and BSP, their observed permeation profiles were comparable and their MAT (mean absorption time) showed no significant difference, which both demonstrated these two drugs achieved the synchronous skin permeation in their compound patch by the dual-directional regulation strategy of combining the technique of ion-pair complexation with chemical enhancers.

Formulation and in vitro evaluation of fast dissolving tablets of metoprolol tartrate

The demand for fast dissolving tablets has been growing during the last decade, especially for elderly and children who have swallowing difficulties. In the present work, fast dissolving tablets of metoprolol tartrate, were prepared using sodium starch glycolate, sodium croscarmellose and crospovidone as superdisintegrants, by the direct compression method. The tablets prepared were evaluated for various parameters including weight variation, hardness, friability, in vitro dispersion time, drug-polymer interaction, drug content water absorption ratio, wetting time, in vitro drug release, FTIR and DSC studies. The tablets prepared by the direct compression method had a weight variation in the range of 145 mg to 152 mg, which is below ± 7.5%, a hardness of 3.6 kg/cm² to 4.5 kg/cm², percentage friability of 0.46% to 0.73%, in vitro dispersion time of 18 s to 125 s, drug content uniformity of between 98.12% and 100.03%, a water absorption ratio of 67% to 87%, wetting time of 32 sec. to 64 sec., and an in vitro drug release of 53.92% - 98.82% within 15 min. The IR spectral analysis and DSC study showed no drug interaction with formulation additives of the tablet, and the formulations indicated no significant changes in hardness, friability, drug content or in vitro drug release. Fast dissolving tablets of metoprolol tartrate have enhanced dissolution and will lead to improved bioavailability and more effective therapy.

A exigência por comprimidos de dissolução rápida aumentou durante a última década, especialmente para idosos e crianças, com dificuldades de deglutição . No presente trabalho prepararam-se, pelo método de compressão direta, comprimidos de tartarato de metoprolol de rápida dissolução, utilizando glicolato sódico de amido, croscarmellose sódica e crospovidona como superdisintegrantes. Os comprimidos preparados foram avaliados em relação a diferentes parâmetros, como variação de peso, dureza, friabilidade, tempo de dispersão in vitro, interação fármaco-polímero, taxa de absorção de água pelo fármaco, tempo de umedecimento, liberação do fármaco in vitro,, FTIR e estudos de DSC. Os comprimidos preparados por compressão direta apresentaram variação de peso de 145 mg a 152 mg, abaixo de ±7,5%, dureza de 3,6 kg/cm² a 4,5 kg/cm² , porcentagem de friabilidade de 0,46% a 0,73%, tempo de dispersão in vitro de 18 s a 125 s, uniformidade de conteúdo de fármaco entre 98,12% e 100,03%, taxa de absorção de água de 67% a 87%, tempo de umidificaçãode 32 s a 64 s liberação do fármaco in vitro entre 53,92% e 98,82%, em 15 min. A análise no IV e de DSC mostrou que não houve interação de fármacos com os aditivos de formulação do comprimido e as formulações indicaram que não houve mudança significativa na dureza, friabilidade, s uniformidade de conteúdo de fármaco e na liberação do fármaco in vitro. Os comprimidos de liberação rápida apresentaram aumento na dissolução de tartarato metoprolol e conduzem à melhoria dabiodisponibilidade e à terapia eficaz.

Structure and activity relationships of tartrate-based TACE inhibitors.

The syntheses and structure-activity relationships of the tartrate-based TACE inhibitors are discussed. The optimization of both the prime and non-prime sites led to compounds with picomolar activity. Several analogs demonstrated good rat pharmacokinetics.

Sorption of tartrate, citrate, and EDTA onto chitosan and its regeneration applying electrolysis.

The equilibrium isotherm data obtained by the sorption of tartrate, citrate, and EDTA onto chitosan were analyzed using Langmuir and Freundlich equations. The process fits best the Langmuir equation. Kinetic investigations showed that the sorption process obeys the pseudo-second-order kinetic equation. Sorption and desorption peculiarities, FTIR investigations, and measurements of molecular weight enable one to hypothesize that sorption proceeds along with the electrostatic interaction between the positively charged -NH3+ groups of chitosan and the negatively charged -COO(-) of carboxylic acids in the formation of amide bonds between the -NH(2) groups of chitosan and the -COOH groups of the carboxylic acid. Electrolysis under galvanostatic conditions in a mixture of chitosan with a 0.1 mol L(-1) Na(2)SO(4) solution enables one to destroy the amide bonds in the cathode compartment of the electrochemical cell and to anodize organics in the anodic compartment. The choosing of relevant conditions of electrolysis enables one to obtain chitosan with properties (deacetylation degree, molecular weight, and sorption ability) similar to those of initial chitosan. After electrolysis the regenerated chitosan possesses the same or even higher ability for sorption of the carboxylic acids as the initial chitosan.

Effects of acute versus chronic L-carnitine L-tartrate supplementation on metabolic responses to steady state exercise in males and females.

Twelve healthy active subjects (6 male, 6 female) performed 60 min of exercise (60% VO(2max)) on 3 occasions after supplementing with L-Carnitine L-tartrate (LCLT) or placebo. Each subject received a chronic dose, an acute dose, and placebo in a randomized, double-blind crossover design. Dietary intake and exercise were replicated for 2 d prior to each trial. In males there was a significant difference in rate of carbohydrate (CHO) oxidation between placebo and chronic trials (P = 0.02) but not placebo and acute trials (P = 0.70), and total CHO oxidation was greater following chronic supplementation vs. placebo )mean +/- standard deviation) of 93.8 (17.3) g/hr and 78.2 (23.3) g/h, respectively). In females, no difference in rate of, or total, CHO oxidation was observed between trials. No effects on fat oxidation or hematological responses were noted in either gender group. Under these experimental conditions, chronic LCLT supplementation increased CHO oxidation in males during exercise but this was not observed in females.

Oral bioavailability in pigs of a miconazole/hydroxypropyl-gamma-cyclodextrin/L-tartaric acid inclusion complex produced by supercritical carbon dioxide processing.

The objective of this study was to determine the pharmacokinetic parameters of miconazole after oral administration of a miconazole/hydroxypropyl-gamma-cyclodextrin(HPgammaCD)/L-tartaric acid inclusion complex produced by supercritical carbon dioxide processing. The pharmacokinetics of the miconazole ternary complex (CPLX), of the corresponding physical mixture (PHYS), and of miconazole alone (MICO) were compared after oral administration. Six mixed-breed pigs received each formulation as a single dose (10 mg miconazole/kg) in a crossover design. Miconazole plasma concentrations were determined by a high-performance liquid chromatography method. Preliminary in vitro dissolution data showed that CPLX exhibits a faster and higher dissolution rate than either PHYS or MICO. Following CPLX oral administration, mean area under the plasma concentration curve (AUC(0-infinity)) for miconazole was 95.0 +/- 55.8 microg/min/mL, with the peak plasma concentration (C(max) 0.59 +/- 0.39 microg/mL) at 19.30 minutes. The AUC(0-infinity) and C(max) values were significantly higher than those after oral administration of PHYS (AUC(0-infinity) 38.5 +/- 12.7 microg/min/mL and C(max) 0.24 +/- 0.08 microg/mL; P < .1) and of MICO (AUC(0-infinity) 24.1 +/- 14.0 microg/min/mL and C(max) 0.1 +/- 0.05 microg/mL; P < .1). There were also significant differences between PHYS and MICO (P < .1). The results of the study indicate that CPLX shows improved dissolution properties and a higher relative oral bioavailability compared with PHYS and MICO.

Boronic acid receptors for alpha-hydroxycarboxylates: high affinity of Shinkai's glucose receptor for tartrate.

The glucose receptor 1 developed by Shinkai was synthesized by known methods and with modifications involving the final synthetic step, installation of the phenylboronic acid moieties. Binding of the bis(alpha-hydroxycarbolxylate), tartrate, was assessed and compared to the corresponding bis(diol), erythritol, as well as the corresponding mono(alpha-hydoxycarboxylate), malate. These results suggest that bisboronate/bis(alpha-hydoxycarboxylate) interactions are stronger than the corresponding bisboronate/bis(diol) interactions. Furthermore, we report that the receptor is an order of magnitude more selective for tartrate than malate.

Different pharmacokinetics of nicotine following intravenous administration of nicotine base and nicotine hydrogen tartarate in rats.

Pharmacokinetics of nicotine was studied in rats following intravenous (i.v.) administration of nicotine base (NB) and nicotine hydrogen tartarate salt (NS) at a nicotine dose of 1 mg/kg. The area under the plasma concentration-time curve (AUC), mean residence time (MRT), systemic clearance (CL), distribution volume at steady state (V(ss)) and terminal plasma half-life (T(1/2,beta)) of nicotine were compared between NB and NS. Compared to NS, NB exhibited higher and sustained plasma nicotine levels, thereby yielding significantly (P<0.05) larger AUC (66.3 vs. 27.7 microg ml/min), MRT (165.7 vs. 58.3 min), T(1/2,beta) (144.2 vs. 51.4 min) and a lower CL (18.3 vs. 46.3 ml/min per kg). The V(ss) was comparable between the two compounds. The metabolic conversion to cotinine from NS was threefold larger than that from NB. The plasma protein binding and distribution to blood cells were comparable between the compounds. The apparent partition coefficient (APC) of NS decreased as a function of its concentration, while that of NB remained nearly constant. Particles of different mean sizes were observed for the 1% (w/v) aqueous solutions of NS (388.6 nm) and NB (123.8 nm). Different metabolism and/or elimination between NB and NS appear to be mainly responsible for their different pharmacokinetics.

Aluminum speciation studies in biological fluids. Part 6. Quantitative investigation of aluminum(III)-tartrate complex equilibria and their potential implications for aluminum metabolism and toxicity.

Recent epidemiological studies have confirmed the existence of a correlation between aluminum level in low-silica drinking water and prevalence of Alzheimer's disease. Also, oral aluminum-based phosphate binders and antacids may induce acute aluminum toxicity. Whatever the source of the metal ingested, its bioavailability is a function of the chemical forms under which it occurs in the gastrointestinal tract, i.e. of the ligands with which the Al3+ ion may associate. Dietary acids in particular can favor the bioavailability of aluminum in different ways: by increasing its solubility, by complexing it into neutral species, and/or by acting indirectly on its absorption process. Among these, tartaric acid is commonly found in fruits and in industrial foods and drinks, and may therefore be ingested together with environmental or/and therapeutic aluminum. The present work examines its potential influence on aluminum bioavailability. Firstly, Al(III)-tartrate complex formation constants have been determined under physiological conditions (37 degrees C, 0.15 M NaCl). Then these constants have been used to simulate the influence of tartrate on aluminum speciation in different gastrointestinal situations in which phosphate was also taken into account. Under normal conditions of aluminum contamination, tartrate is expected to keep the metal soluble throughout the whole pH range of the small intestine, which is likely to enhance its bioavailability. Even at low concentrations, tartrate also gives rise to two neutral complexes that span over the 1.5-7.5 pH interval, a phenomenon that is aggravated by increased aluminum levels as may result from aluminum hydroxide therapy. The co-occurrence of dietary phosphate reduces the fraction of aluminum neutralized by tartrate under normal conditions, but this effect quickly decreases with increasing aluminum doses. Even the therapeutic use of aluminum phosphate is not expected to be totally safe in the presence of tartaric acid. As plasma simulations show that no aluminum mobilization can be expected from tartrate that could enhance aluminum excretion, avoiding ingestion of tartaric acid during any form of aluminum-based therapy appears advisable.

Bioavailability and intestinal absorption of aluminum in rats: effects of aluminum compounds and some dietary constituents.

In the present investigation, the deposition of aluminum in intestinal fragment and the appearance in blood were studied in a perfused rat intestine in situ for 1 h with several aluminum forms (16 mM). We observed that aluminum absorption was positively correlated with the theoretic affinity of aluminum and the functional groups of the chelating agent. The absorption of aluminum after ingestion of organic compounds is more important than after ingestion of mineral compounds, with the following order: Al citrate > Al tartrate, Al gluconate, Al lactate > Al glutamate, Al chloride, Al sulfate, Al nitrate. Absorption depends on the nature of the ligands associated with the Al3+ ion in the gastrointestinal fluid. The higher the aluminum retention in intestinal fragment, the lower the absorption and appearance in blood. However, the higher aluminum concentration is always in the jejunal fragment because of the influence of pH variation on this fragment. Another objective of the present study was to determine the influence of several parameters on aluminum citrate absorption: with or without 0.1 mmol dinitrophenol/L, with aluminum concentration from 3.2, 16, 32, and 48, to 64 mmol/L, media containing 0, 3, or 6 mmol Ca/L, with or without phosphorus or glucose. It is concluded that aluminum is absorbed from the gastrointestinal tract by (1) a paracellular energy independent and nonsaturable route, mainly used for high aluminum concentration, which is modified by extracellular calcium, and (2) a transcellular and saturable route, the aluminum level was not modified with enhancement of aluminum quantity in intestinal lumen. This pathway can be similar with calcium transfer through the intestine and is energy dependent because of a decrease of aluminum absorption that follows the removal of glucose and phosphorus.

Desenvolvimento e avaliaçäo ®in vitro¼ de comprimidos de liberação controlada de tartarato de metoprolol / Development and evaluation ®in vitro¼ of controlled release tablets of metoprolol tartrate

O objetivo do trabalho foi obter comprimidos de liberação controlada não desintegráveis contendo o bloqueador ßi-adrenéergico, tartarato de metoprolol, empregando-se carboximetilcelulose 1-5000cps (CMC), hidroxipropilmetilcelulose 100.000cps (Methocel© K100), polímeros metacrilatos (Eudragit© NE30D e RS30D), etilcelulose (Ethocel© 10 e 100cps) e ácido esteárico como modificadores da liberação. Os comprimidos foram submetidos a testes de dissolução em meio gástrico e intestinal, simulado sem enzimas, conforme a Farmacopéia Americana 24 ed. (aparelho 2), e por variação de pH para avaliação dos perfis e cinéticas de dissolução. Os comprimidos produzidos com polímeros hidrofílicos (CMC, Methocel©) hidrataram-se rapidamente com a liberação do fármaco, sendo controlado pela difusão através da matriz intumescida e gelificada...

In vitro and in vivo assessment of the bioavailability of potassium from a potassium tartrate tablet.

The bioavailability of potassium from orally administered potassium tartrate was evaluated in 20 normal subjects under metabolic balance conditions. Subjects were given 34 mmol potassium (5 tablets of Cal-K) as a divided dose on each of 2 consecutive days. Urinary excretion of potassium, as determined from 24-h urinary collections on the 3 days preceding dosage totalled 192.6 +/- 50.9 mmol (mean +/- S.D., n = 20). It increased significantly (p less than 0.05) to 258.7 +/- 54.2 mmol for the 2 days of dosage and the following day. The difference of 66.1 mmol representing absorbed potassium was close to the 68 mmol potassium given and indicated a bioavailability of potassium in excess of 97 per cent; after correction for creatinine excretion, potassium recovery rose to 99.9 per cent. The dissolution characteristics of the Cal-K tablets were also determined. After dissolution in simulated gastric juice (pH 1.2), 84.4 +/- 10.6 per cent (mean +/- S.D., 6 experiments) was dissolved; after adjustment to pH 7.3, dissolved potassium increased to 91.3 +/- 8.5 per cent. No precipitation or residue formed as a result of the pH change. Both sets of results indicate that potassium from these potassium tartrate tablets is in a highly bioavailable form.

Absorption of water and solute from glucose-electrolyte solutions in the human jejunum: effect of citrate or betaine.

The inclusion in oral rehydration solutions of solutes that are actively co-transported with sodium has been suggested as a means of increasing the effect of glucose on water absorption by the small intestine. Using a modified perfusion system we have examined water and solute absorption in the normal human intestine from two effervescent glucose-electrolyte solutions, containing either citrate or betaine hydrochloride, and compared the absorption rates with those from a commonly used bicarbonate-containing oral rehydration solution. Absorption of citrate (355 +/- 87 mumol/cm/h) and betaine (313 +/- 125 mumol/cm/h) occurred from the respective solutions. The inclusion of 46 mmol/l citrate or 36 mmol/l betaine in effervescent oral rehydration solutions had no effect on water or solute absorption.