The influence of dietary protein deficiency on pharmacokinetics and pharmacodynamics of furosemide was investigated after i.v. bolus (1 mg/100 g) and oral (2 mg/100 g) administration of furosemide to male Sprague-Dawley rats fed on a 23% (control) or a 5% (protein-calorie malnutrition: PCM) protein diet ad lib. for 4 weeks. After i.v. administration, the mean values of CLR, Vss, and the percentages of dose excreted in 8-hr urine as furosemide were increased 81, 31, and 61%, respectively, in PCM rats when compared with those in control rats, however, CLNR was 54% decreased in PCM rats. The decreased CLNR in PCM rats suggested the significantly decreased nonrenal metabolism of furosemide. The urine volume per g kidney after i.v. administration was not significantly different between the two groups of rats although the amount of furosemide excreted in 8-hr urine per g kidney increased significantly in PCM rats. The diuretic, natriuretic, kaliuretic, and chloruretic efficiencies reduced significantly in PCM rats after i.v. administration. After oral administration, the extent of bioavailability increased considerably from 27.6% in control rats to 47.0% in PCM rats, probably as a result of decreased gastrointestinal and hepatic first-pass metabolism. This was supported by a tissue homogenate study; the amount of furosemide remaining per g tissue after 30-min incubation of 50 micrograms of furosemide with the 9000 x g supernatant fraction of stomach (42.4 vs. 47.9 micrograms) and liver (41.4 vs. 45.9 micrograms) homogenates increased significantly in PCM rats. No significant differences in CLR and t1/2 were found between the control and the PCM rats after oral administration. The 24-hr urine volume and the amount of sodium excreted in 24-hr urine per g kidney increased significantly in PCM rats, and this might be due to a significantly increased amount of furosemide reaching the kidney excreted in urine per g kidney.

Various factors influencing the protein binding of DA-8159 to 4% human serum albumin (HSA) were evaluated using an equilibrium dialysis technique at an initial DA-8159 concentration of 5 microg/mL. It took approximately 8 h incubation to reach an equilibrium between 4% HSA and an isotonic phosphate buffer of pH 7.4 containing 3% of dextran ('the buffer') using a Spectra/Por 2 membrane (mol. wt. cut-off: 12,000--14,000) in a water bath shaker kept at 37 degrees C and at a rate of 50 oscillations per min. The extent of binding was dependent on DA-8159 concentrations, HSA concentrations, incubation temperature, buffer pH, and alpha-1-acid glycoprotein (AAG) concentrations. The binding of DA-8159 in heparinized human plasma (93.9%) was significantly higher than in rats (81.4%), rabbits (80.4%), and dogs (82.2%), and this could be due to differences in AAG concentrations in plasma.

Since considerable first-pass effects of azosemide have been reported after oral administration of the drug to rats and man, first-pass effects of azosemide were evaluated after intravenous, intraportal and oral administration, and intraduodenal instillation of the drug, to rats. The total body clearances of azosemide after intravenous (5 mg kg-1) and intraportal (5 and 10 mg kg-1) administration of the drug to rats were considerably smaller than the cardiac output of rats suggesting that the lung or heart first-pass effect (or both) of azosemide after oral administration of the drug to rats was negligible. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) after intraportal administration (5 mg kg-1) of the drug was significantly lower than that after intravenous administration (5 mg kg-1) of the drug (1000 vs 1270 micrograms min mL-1) suggesting that the liver first-pass effect of azosemide was approximately 20% in rats. The AUC from time 0 to 8 h (AUC0-8 h) after oral administration (5 mg kg-1) of the drug was considerably smaller than that after intraportal administration (5 mg kg-1) of the drug (27.1 vs 1580 micrograms min mL-1) suggesting that there are considerable gastrointestinal first-pass effects of azosemide after oral administration of azosemide to rats. Although the AUC0-8 h after oral administration (5 mg kg-1) of azosemide was approximately 15% lower than that after intraduodenal instillation (5 mg kg-1) of the drug (27.1 vs 32.0 micrograms min mL-1), the difference was not significant, suggesting that the gastric first-pass effect of azosemide was not considerable in rats. Azosemide was stable in human gastric juices and pH solutions ranging from 2 to 13. Almost complete absorption of azosemide from whole gastrointestinal tract was observed after oral administration of the drug to rats. The above data indicated that most of the orally administered azosemide disappeared (mainly due to metabolism) following intestinal first-pass in rats.

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Because physiological changes occurring in diabetes patients could alter the pharmacokinetics of drugs used to treat the disease, the pharmacokinetics and tissue distribution of DA‐1131, a new carbapenem antibiotic, were investigated after 1‐min intravenous (iv) administration of the drug, 50 mg kg−1, to control and alloxan‐induced diabetes mellitus (AIDM) rats. The impaired kidney function was observed by pretreatment with alloxan based on physiological parameters of plasma, creatinine clearance, and the kidney microscopy. After 1‐min iv infusion of DA‐1131, the plasma concentrations of DA‐1131 and the total area under the plasma concentration–time curve of DA‐1131 from time zero to time infinity (AUC) increased significantly in the AIDM rats (7350 versus 4400 μg min mL−1) when compared with those in control rats. This was due to significantly slower total body clearance (Cl) of DA‐1131 (6.80 versus 11.4 mL min−1 kg−1) in AIDM rats than that in control rats. The significantly slower Cl of DA‐1131 in AIDM rats was due to significantly slower renal (2.62 versus 4.95 mL min−1 kg−1, because of the considerably decreased glomerular filtration rate of DA‐1131) and nonrenal (3.99 versus 6.34 mL min−1 kg−1, possibly because of the considerably slower metabolism in rat liver and kidney) clearance in AIDM rats. The amount of DA‐1131 recovered from each rat tissue studied was significantly higher in AIDM rats than that in control rats, however, the tissue to plasma ratios were not significantly different between the two groups of rats. © 1998 John Wiley & Sons, Ltd.