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.

No abstract

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.

The pharmacokinetic and pharmacodynamic parameters of torasemide were compared after intravenous administration at a dose of 2 mg/kg to diabetic rats induced by alloxan (DMIA) or streptozotocin (DMIS), and their respective control rats. It was reported that torasemide was mainly metabolized via CYP2C11 in rats and the expression and mRNA level of CYP2C11 decreased in DMIA and DMIS rats. Hence, it could be expected that the time-averaged nonrenal clearance (Cl(nr)) of torasemide could be slower in the diabetic rats. As expected, the Cl(nr) values were significantly slower in DMIA (0.983 versus 1.35 ml/min/kg) and DMIS (0.998 versus 1.36 ml/min/kg) rats. However, the time-averaged renal clearance (Cl(r)) values of torasemide were significantly faster in DMIA (0.164 versus 0.0846 ml/min/kg) and DMIS (0.205 versus 0.0967 ml/min/kg) rats due to urine flow rate-dependent timed-interval Cl(r) of torasemide in rats. The comparable time-averaged total body clearance (Cl) values between the diabetic and control rats were due to partially compensated Cl(r) in the diabetic rats. The 8 h urine output and diuretic efficiency increased significantly in the diabetic rats due to significantly greater 8 h urinary excretion of unchanged torasemide and at least partly due to an increase in urine output in diabetes per se (without administration of any drugs).

The pharmacokinetic parameters including tissue distribution and/or biliary excretion of DA‐1131, a new carbapenem, were evaluated after intravenous (iv) administration to mice, rats, rabbits, and dogs. After iv administration to mice (20, 50, 100, and 200 mg kg−1), rats (50, 100, 200, and 500 mg kg−1), rabbits (20, 50, 100, and 200 mg kg−1), and dogs (10, 20, 50, 100, and 200 mg kg−1), the pharmacokinetic parameters of DA‐1131 seemed to be independent of DA‐1131 doses studied in all four animal species. However, the renal clearance and percentage of iv dose of DA‐1131 excreted in 24 h urine as unchanged drug decreased significantly in rabbits (from 200 mg kg−1) and dogs (from 100 mg kg−1) due to reduced kidney function induced by DA‐1131. The creatinine clearance decreased significantly in rabbits at 200 mg kg−1 compared with that in the control rabbits (0.466 versus 4.31 mL min−1 kg−1). Renal active secretion of DA‐1131 was observed in rabbits and was less considerable in rats, but renal active reabsorption of DA‐1131 was observed in dogs. Although DA‐1131 was widely distributed in all tissues studied in mice (20–200 mg kg−1), rats (200 mg kg−1), rabbits (50 mg kg−1), and dogs (50 mg kg−1), affinity of DA‐1131 for tissues was low: the tissue‐to‐plasma concentration ratios were greater than unity only in the kidney and/or liver. The low affinity of DA‐1131 for tissues was also supported by relatively low values of the apparent volume of distribution at steady state in rats (147–187 mL kg−1), rabbits (91.7–148 mL kg−1), and dogs (243–298 mL kg−1). The contribution of biliary excretion of unchanged DA‐1131 to nonrenal clearance of DA‐1131 seemed to be minor in rats (200 mg kg−1) and dogs (50 mg kg−1); the percentages of iv dose excreted in 8 h bile as unchanged DA‐1131 were 1.76 and 2.71% after iv administration of the drug to rats and dogs, respectively. © 1998 John Wiley & Sons, Ltd.

Because the physiological changes that occur in patients with acute renal failure could alter the pharmacokinetics of the drugs used to treat the disease, the pharmacokinetics of DA-1131, a new carbapenem antibiotic, were investigated after 1-min intravenous administration of the drug (50 mg/kg of body weight) to control rats and rats with uranyl nitrate-induced acute renal failure (U-ARF rats). The impaired kidney function was observed in U-ARF rats on the basis of physiological parameters observed by microscopy of the kidney and obtained by chemical analysis of the plasma. After a 1-min intravenous infusion of DA-1131, the concentrations in plasma and the total area under the plasma concentration-time curve from time zero to time infinity increased significantly in U-ARF rats compared with those in control rats (13,000 versus 4,400 μg · min/ml). This was due to the significantly slower total body clearance (CL) of DA-1131 (3.84 versus 11.4 ml/min/kg) from U-ARF rats than from control rats. The significantly slower CL of DA-1131 from U-ARF rats was due to both significantly slower renal clearance (0.000635 versus 4.95 ml/min/kg because of a significant decrease in the 8-h urinary excretion of unchanged DA-1131 [1.54 versus 43.8% of the intravenous dose] due to impaired kidney function, as proved by the significant decrease in creatinine clearance [0.0159 versus 4.29 ml/min/kg]) and significantly slower nonrenal clearance (3.80 versus 6.34 ml/min/kg because of a significant decrease in the metabolism of DA-1131 in the kidney) in U-ARF rats. The amounts of DA-1131 recovered from all tissues studied (except the kidneys) were significantly higher for U-ARF rats than for control rats; however, the ratios of the amount in tissue to the concentration in plasma (except those for the kidney, small intestine, and spleen) were not significantly different between the two groups of rats, indicating that the affinity of DA-1131 for rat tissues was not changed considerably in U-ARF rats.