The Experts below are selected from a list of 111 Experts worldwide ranked by ideXlab platform
Masayuki Isaji - One of the best experts on this subject based on the ideXlab platform.
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sergliflozin a novel selective inhibitor of low affinity sodium glucose coTransporter sglt2 validates the critical role of sglt2 in renal glucose reabsorption and modulates plasma glucose level
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Kenji Katsuno, Yoshikazu Fujimori, Yukiko Takemura, Masahiro Hiratochi, Fumiaki Itoh, Yoshimitsu Komatsu, Hideki Fujikura, Masayuki IsajiAbstract:The low-affinity sodium glucose coTransporter (SGLT2), which is expressed specifically in the kidney, plays a major role in renal glucose reabsorption in the proximal tubule. We have discovered sergliflozin, a prodrug of a novel selective SGLT2 inhibitor, based on benzylphenol glucoside. In structure, it belongs to a new category of SGLT2 inhibitors and its skeleton differs from that of phlorizin, a nonselective SGLT inhibitor. We investigated its pharmacological properties and potencies in vitro and in vivo. By examining a Chinese hamster ovary-K1 cell line stably expressing either human SGLT2 or human high-affinity sodium glucose coTransporter (SGLT1), we found sergliflozin-A (active form) to be a highly selective and potent inhibitor of human SGLT2. At pharmacological doses, sergliflozin, sergliflozin-A, and its aglycon had no effects on facilitative glucose Transporter 1 activity, which was inhibited by phloretin (the aglycon of phlorizin). The Transport Maximum for glucose in the kidney was reduced by sergliflozin-A in normal rats. As a result of this effect, orally administered sergliflozin increased urinary glucose excretion in mice, rats, and dogs in a dose-dependent manner. In an oral glucose tolerance test in diabetic rats, sergliflozin exhibited glucose-lowering effects independently of insulin secretion. Any glucose excretion induced by sergliflozin did not affect normoglycemia or electrolyte balance. These data indicate that selective inhibition of SGLT2 increases urinary glucose excretion by inhibiting renal glucose reabsorption. As a representative of a new category of antidiabetic drugs, sergliflozin may provide a new and unique approach to the treatment of diabetes mellitus.
Kenji Katsuno - One of the best experts on this subject based on the ideXlab platform.
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sergliflozin a novel selective inhibitor of low affinity sodium glucose coTransporter sglt2 validates the critical role of sglt2 in renal glucose reabsorption and modulates plasma glucose level
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Kenji Katsuno, Yoshikazu Fujimori, Yukiko Takemura, Masahiro Hiratochi, Fumiaki Itoh, Yoshimitsu Komatsu, Hideki Fujikura, Masayuki IsajiAbstract:The low-affinity sodium glucose coTransporter (SGLT2), which is expressed specifically in the kidney, plays a major role in renal glucose reabsorption in the proximal tubule. We have discovered sergliflozin, a prodrug of a novel selective SGLT2 inhibitor, based on benzylphenol glucoside. In structure, it belongs to a new category of SGLT2 inhibitors and its skeleton differs from that of phlorizin, a nonselective SGLT inhibitor. We investigated its pharmacological properties and potencies in vitro and in vivo. By examining a Chinese hamster ovary-K1 cell line stably expressing either human SGLT2 or human high-affinity sodium glucose coTransporter (SGLT1), we found sergliflozin-A (active form) to be a highly selective and potent inhibitor of human SGLT2. At pharmacological doses, sergliflozin, sergliflozin-A, and its aglycon had no effects on facilitative glucose Transporter 1 activity, which was inhibited by phloretin (the aglycon of phlorizin). The Transport Maximum for glucose in the kidney was reduced by sergliflozin-A in normal rats. As a result of this effect, orally administered sergliflozin increased urinary glucose excretion in mice, rats, and dogs in a dose-dependent manner. In an oral glucose tolerance test in diabetic rats, sergliflozin exhibited glucose-lowering effects independently of insulin secretion. Any glucose excretion induced by sergliflozin did not affect normoglycemia or electrolyte balance. These data indicate that selective inhibition of SGLT2 increases urinary glucose excretion by inhibiting renal glucose reabsorption. As a representative of a new category of antidiabetic drugs, sergliflozin may provide a new and unique approach to the treatment of diabetes mellitus.
Thomas Frenzel - One of the best experts on this subject based on the ideXlab platform.
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Biliary Excretion and Pharmacokinetics of a Gadolinium Chelate Used as a Liver-Specific Contrast Agent for Magnetic Resonance Imaging in the Rat
Journal of pharmaceutical sciences, 1993Co-Authors: Gabriele Schuhmann-giampieri, Heribert Schitt-willich, Thomas FrenzelAbstract:The introduction of a lipophilic moiety into the gadolinium chelate Gd-DTPA (dimeglumine gadopentetate, Magnevist) yielded Gd-EOB-DTPA (short form), which has potential as a magnetic resonance contrast agent for liver mass screening. The pharmacokinetics of Gd-EOB-DTPA in rats is nonlinear because after correction for the 10-fold difference in dose, the area under the curve of plasma concentration versus time from time zero to infinity after single intravenous application of two different doses were not superimposable, and the amounts excreted renally and extrarenally differed significantly. However, for both dose groups tested, the values of renal clearance (9.96 and 11.1 mL/min.kg, respectively) were close to the value of glomerular filtration in the rat. Michaelis-Menten kinetics in the extrarenal elimination was therefore considered as the rate-limiting process of Gd-EOB-DTPA, the binding to plasma protein of which is small (10.3 +/- 1.4%). Thus, biliary elimination was significantly inhibited by the intravenous coadministration of sulfobromophthalein (a decrease from 39.5 +/- 3.17 to 30.7 +/- 5.30% of the dose was observed from 0 to 90 min postinoculation under coadministration of the inhibitor), whereas tauroglycocholate revealed no effect, indicating the involvement of the so-called organic anion plasma membrane Transport system for the hepatic uptake. The Transport of Gd-EOB-DTPA from the cytoplasm to the bile is mainly determined by the capacity of the Transport protein glutathione-S-transferase as demonstrated by in vitro binding studies. A hepatobiliary Transport Maximum of 9.2 mumol/min.kg was evaluated by infusion studies. No metabolites were detected either in the bile or in the urine, and enterohepatic circulation can be excluded.
Ulrich Speck - One of the best experts on this subject based on the ideXlab platform.
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preclinical evaluation of gd eob dtpa as a contrast agent in mr imaging of the hepatobiliary system
Radiology, 1992Co-Authors: Gabriele Schuhmanngiampieri, Heribert Schmittwillich, W R Press, C Negishi, H J Weinmann, Ulrich SpeckAbstract:Gadolinium diethylenetriaminepentaacetic acid (DTPA) covalently linked to the lipophilic ethoxybenzyl moiety (Gd-EOB-DTPA) was designed for use as a contrast agent in hepatobiliary magnetic resonance imaging. With T1 relaxivity values of 8.7 L/mmol.second in plasma and 16.6 L/mmol.second in rat liver tissue and a median lethal dose of 10 mmol/kg when administered intravenously in mice and rats, Gd-EOB-DTPA has a fairly high margin of safety. In rats and monkeys, biodistribution studies performed 7 days after administration of 0.25 mmol/kg revealed very little retention of gadolinium (less than 1%) in the tissues, indicating complete elimination via renal and biliary excretion. Biliary excretion was inhibited by coadministration of sulfobromophthalein, indicating the involvement of a carrier-mediated Transport system based on the enzyme glutathione-S-transferase. In rats, the biliary Transport Maximum was 5 mumol gadolinium/min.kg. High T1 relaxivity of Gd-EOB-DTPA in rat liver in vivo can be explained by ...
I. Janků - One of the best experts on this subject based on the ideXlab platform.
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Physiological modelling of renal drug clearance
European Journal of Clinical Pharmacology, 1993Co-Authors: I. JankůAbstract:A physiological model of renal drug clearance is presented with the aim of establishing a basis for adjusting drug dosing regimens in renal insufficiency. In agreement with the morphology of blood supply to the nephron, the model assumes serial arrangement of the processes involved in drug excretion. Fractional extraction by filtration in the glomeruli is defined in terms of the product of the unbound fraction of the drug, the filtration fraction being responsible for the limited extraction efficiency of this process. For a description of the limitations of the tubular secretory process by plasma flow through peritubular capillaries, the parallel tube model is utilized. The assumption of direct proportionality between the Transport Maximum of the secretory process and filtrate flow in the tubules permits a quantitative comparison of the intrinsic tubular secretion clearance and the effectiveness of the filtration process. Provided that the secretory mechanism is highly effective, renal clearance becomes dependent only on kidney plasma flow and the fraction of drug not reabsorbed in the tubules. Tubular reabsorption results only in a proportional decrease in renal clearance. The model predicts proportionality of renal drug clearance to GFR, which as a rule is used for dosage adjustment of drugs in renal insufficiency, only for compounds exclusively excreted by filtration. Compounds also excreted by tubular secretion in general exhibit a curvilinear relationship. The curvature is less pronounced as an increasing fraction of the drug is protein bound in blood. Therefore, for dosage adjustment of drugs secreted in the tubules and highly bound in blood, proportionality between renal clearance and GFR can serve as a reasonable approximation. According to the model, distinct deviations from simple proportionality, which will require dosage adjustment methods involving assessment both of glomerular and tubular functions of the kidney, can be expected mainly for drugs for which an efficient flow-dependent secretion process is not counteracted by extensive binding of the drug to blood constituents.
