ABSTRACT:This paper reports 1) the increase in expression of CYP1A2 in mutant Nagase analbuminemic rats (NARs), 2) the role of globulin binding of azosemide in circulating blood in its urinary excretion and hence its diuretic effects in NARs, and 3) the significantly faster renal (CL R ) and nonrenal (CL NR ) clearances of azosemide in NARs. Azosemide (mainly metabolized via CYP1A2 in rats), 10 mg/kg, was intravenously administered to control rats and NARs. Northern and Western blot analyses revealed that the expression of CYP1A2 increased ϳ3.5-fold in NARs as compared with control. The plasma protein binding of azosemide in control rats and NARs was 97.9 and 84.6%, respectively. In NARs, plasma protein binding (84.6%) was due to binding to ␣-(82.6%) and ␤-(68.9%) globulins. In NARs, the amount of unchanged azosemide excreted in 8-h urine was significantly greater (37.7 versus 21.0% of intravenous dose) than that in control rats due to an increase in intrinsic renal active secretion of azosemide. Accordingly, the 8-h urine output was significantly greater in NARs. The area under the plasma concentration-time curve of azosemide was significantly smaller (505 versus 2790 g ⅐ min/ml) in NARs because of markedly faster CL R (7.36 versus 0.772 ml/min/kg, secondary to a significant increase in urinary excretion of azosemide and intrinsic renal active secretion). Additionally, CL NR was significantly faster (12.4 versus 3.05 ml/min/kg, because of ϳ3.5 fold increase in CYP1A2) in NARs compared with control. Based on in vitro hepatic microsomal studies, the intrinsic M1 [a metabolite of azosemide; 5-(2-amino-4-chloro-5-sulfamoylphenyl)-tetrazole] formation clearance was significantly faster (67.0% increase) in NARs than that in control rats, and this supports significantly faster CL NR in NARs. Renal sensitivity to azosemide was significantly greater in NARs than in control rats with respect to 8-h urine output (385 versus 221 ml/kg) and 8-h urinary excretions of sodium, potassium, and chloride. This study supports that in NARs, binding of azosemide to ␣-and ␤-globulins in circulating blood play an important role in its diuretic effects.Azosemide 1 [5-(4-chloro-5-sulfamoyl-2-thenylaminophenyl)-tetrazole] is a sulfonamide loop diuretic closely resembling furosemide in its diuretic action (Krück et al., 1978). Its main sites of action are both the cortical and medullary segments of the thick ascending limb of loop of Henle (Brater, 1979) where it inhibits water and solute reabsorption. It is used clinically in the treatment of edematous states and arterial hypertension; specific indications are cardiac and renal edema and ascites (Michel, 1992). Eleven metabolites of azosemide were found in rat urine and bile (Asano et al., 1984), but the diuretic effect of the drug does not require metabolism to an active metabolite (Greven, 1991).After i.v. administration of furosemide to mutant Nagase analbuminemic rats (NARs), an animal model for human familial analbuminemia, the diuretic effects of the drug (urine output and urinary e...

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The importance of plasma protein binding of intravenous furosemide in circulating blood for its urinary excretion and hence its diuretic effects in mutant Nagase analbuminemic rats was reported. Based on the furosemide report, the diuretic effects of another loop diuretic, bumetanide, could be expected in analbuminemic rats if plasma protein binding of bumetanide is considerable in the rats. This was proved by this study. After intravenous administration of bumetanide, 10 mg/kg, to analbuminemic rats, the plasma protein binding of bumetanide was 36.8% in the rats mainly due to considerable binding to alpha- and beta-globulins (this value, 36.8%, was considerably greater than only 12% for furosemide), and hence the percentages of intravenous dose of bumetanide excreted in 6 h urine as unchanged drug was 16.0% in the rat (this value was considerably greater than only 7% for furosemide). After intravenous administration of bumetanide to analbuminemic rats, the area under the plasma concentration-time curve from time zero to time infinity (1012 compared with 2472 microg min/mL) was significantly smaller [due to significantly faster both renal clearance (1.49 compared with 0.275 ml/min/kg) and nonrenal clearance (8.30 compared with 3.71 ml/min/kg)], terminal half-life (9.94 compared with 22.4 min) and mean residence time (4.25 compared with 5.90 min) were significantly shorter (due to faster total body clearance, 9.88 compared with 4.05 ml/min/kg), and amount of 6 h urinary excretion of unchanged bumetanide (559 compared with 261 microg, due to increase in intrinsic renal excretion) was significantly greater than that in control rats. The 6 h urine output and 6 h urinary excretions of sodium, chloride and potassium were comparable between two groups of rats although the 6 h urinary excretion of bumetanide was significantly greater in analbuminemic rats. This could be explained by the following. The amount of urinary excretion of bumetanide was significantly greater in analbuminemic rats than that in control rats only between 0 and 30 min urine collection. In both groups of rats, the urinary excretion rates of bumetanide during 0-30 min reached a upper plateau with respect to urine flow rate as well urinary excretion rates of sodium, potassium and chloride, therefore, the diuretic effects (6 h urine output and 6 h urinary excretions of sodium, potassium and chloride) were not significantly different between two groups of rats.

A newly fabricated plasma-polymerized poly(ethylene glycol) (PP-PEG) film shows extremely low toxicity, low fouling, good durability, and chemical similarity to typical PEG polymers, enabling live cell patterning as well as various bioapplications using bioincompatible materials. The PP-PEG film can be overlaid on any materials via the capacitively coupled plasma chemical vapor deposition (CCP-CVD) method using nontoxic PEG200 as a precursor. The biocompatibility of the PP-PEG-coated surface is confirmed by whole blood flow experiments where no thrombi and less serum protein adsorption are observed when compared with bare glass, polyethylene (PE), and polyethylene terephthalate (PET) surfaces. Furthermore, unlike bare PE films, less fibrosis and inflammation are observed when the PP-PEG-coated PE film is implanted into subcutaneous pockets of mice groin areas. The cell-repellent property of PP-PEG is also verified via patterning of mammalian cells, such as fibroblasts and hippocampal neurons. These results show that our PP-PEG film, generated by the CCP-CVD method, is a biocompatible material that can be considered for broad applications in biomedical and functional materials fields.

Pharmacokinetic parameters of DA-7867 were dose independent after both intravenous administration and oral administration (at doses of 1 to 20 mg/kg of body weight) to rats. After oral administration of DA-7867 to rats at a dose of 10 mg/kg, approximately 8.27% of oral dose was not absorbed from the gastrointestinal tract, F was 70.8%, and approximately 21.8% of the oral dose was eliminated by the intestine (intestinal first-pass effect).During the 1980s and 1990s, the emergence and wide spread of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE; Enterococcus faecium and MICs at which 90% of isolates tested are inhibited (MIC 90 s) of DA-7867 were 0.78, 0.2, and 0.39 g/ml for MRSA (n ϭ 37), VRE (E. faecium; n ϭ 36), and PRSP (n ϭ 33), and the corresponding values for linezolid were 3.13, 1.56, and 1.56 g/ml. The MIC 90 s of DA-7867 were 3.13 and 0.78 g/ml for H. influenzae (n ϭ 37) and M. catarrhalis, respectively, which were four-to eightfold lower than those of linezolid. DA-7867 is being evaluated in preclinical studies as a new oxazolidinone antibiotic. The purpose of the present study was to report the dose-independent area under the plasma drug concentrationtime curve from time zero to time infinity (AUC 0-ϱ ) of DA-7867 after intravenous or oral administration to rats of doses of 1, 5, 10, and 20 mg/kg and gastric and intestinal first-pass effects of DA-7867 after intraportal, intragastric, and intraduodenal administration to rats of a dose of 10 mg/kg.DA - Other chemicals were of reagent or HPLC grade and therefore were used without further purification. Male Sprague-Dawley rats (weight, 264 to 310 g) were purchased from Charles River Company Korea (Biogenomics, Seoul, Korea). The animals were maintained in a clean room