Pharmacokinetics and pharmacodynamics of intravenous bumetanide in mutant Nagase analbuminemic rats: importance of globulin binding for the pharmacodynamic effects.

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.     

Pharmacokinetics and pharmacodynamics of intravenous azosemide in mutant Nagase analbuminemic rats.

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 approximately 3.5-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 alpha- (82.6%) and beta- (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 microg. 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 approximately 3.5 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 alpha- and beta-globulins in circulating blood play an important role in its diuretic effects.     

Pharmacokinetics and pharmacodynamics of intravenous torasemide in diabetic rats induced by alloxan or streptozotocin

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).     

Pharmacokinetics of 5-fluorouracil in rats with diabetes mellitus induced by streptozotocin

The pharmacokinetic parameters of 5-fluorouracil were compared after intravenous administration at a dose of 30 mg/kg to control Sprague-Dawley rats and to rats with diabetes mellitus induced by streptozotocin (DMIS). In DMIS rats, the area under the plasma concentration-time curve from time zero to time infinity (AUC) was significantly smaller (603 versus 909 microg min/ml) due to the significantly faster total body clearance (Cl; 47.8 versus 33.0 ml/min/kg). The faster Cl was due to the significantly faster renal (8.54 versus 4.02 ml/min/kg) and nonrenal (38.5 versus 28.7 ml/min/kg) clearances. In DMIS rats, the total amount of unchanged 5-fluorouracil excreted in 24 h urine was significantly greater (34.1% versus 13.0% of intravenous dose) due to the urine flow rate-dependent renal clearance of 5-fluorouracil in rats (the greater the urine flow rate, the greater the urinary excretion of 5-fluorouracil). Greater urinary excretion and a significantly smaller AUC resulted in a significantly faster Cl(r) in DMIS rats. The faster Cl(nr) in DMIS rats could be due to an increase in the expression and mRNA level of CYP1A1/2 in the rats.     

Effects of the rate and composition of fluid replacement on the pharmacokinetics and pharmacodynamics of intravenous torasemide

The effects of differences in the rate and composition of intravenous fluid replacement for urine loss on the pharmacokinetics and pharmacodynamics of torasemide were evaluated in rabbits. Each rabbit received 2-h constant intravenous infusion of 1 mg kg(-1) torasemide with 0% replacement (treatment 1, n=6), 50% replacement (treatment 2, n=9), 100% replacement with lactated Ringer's solution (treatment 3, n=8), and 100% replacement with 5% dextrose in water (treatment 4, n=6). Total body (4.53, 5.72, 10.0 and 4.45 mL min(-1) kg(-1) for treatments 1-4, respectively) and renal clearance (1.44, 1.87, 6.78 and 1.72 mL min(-1) kg(-1)) of torasemide, and total amount of unchanged torasemide excreted in 8-h urine (A(e 0-8 h): 694, 780, 1310 and 1040 microg) in treatment 3 were considerably faster and greater compared with treatments 1, 2 and 4. Although the difference in A(e 0-8 h) between treatments 1 and 3 was only 88.8%, the diuretic and/or natriuretic effects of torasemide were markedly different among the four treatments. For example, the mean 8-h urine output was 101, 185, 808 and 589 mL for treatments 1-4, respectively, and the corresponding values for sodium excretion were 10.1, 20.6, 89.2 and 29.9 mmol, and for chloride excretion were 14.5, 27.9, 94.0 and 37.2 mmol. Although full fluid replacement was used in both treatments 3 and 4, the 8-h diuretic, natriuretic and chloruretic effects in treatment 3 were significantly greater compared with treatment 4, indicating the importance of the composition of fluid replacement. Both treatments 1 and 4 received no sodium replacement, however, the 8-h diuretic, natriuretic and chloruretic effects were significantly greater in treatment 4 compared with treatment 1, indicating the importance of rate of fluid replacement for the diuretic effects. Therefore, the 8-h diuretic, natriuretic and chloruretic effects were significantly greater in treatment 3 compared with treatments 1, 2 and 4, indicating the importance of full fluid and electrolyte replacement. Some implications for the bioequivalence evaluation of dosage forms of torasemide are discussed.     

Diuretic and hypotensive actions of torasemide in hypertensive models of rat

The diuretic and the antihypertensive actions of torasemide were examined in renal and genetic hypertensive rats and compared to the effects of furosemide. Oral administration of torasemide (1 and 3 mg/kg) elicited a dose-dependent increase in the excretion of urine and electrolytes and elevated the urinary Na/K ratio in both renal and genetic hypertensive rats. Torasemide and furosemide had a similar maximum diuretic effect in the normotensive Wistar rat and the spontaneously hypertensive rat (SHR). However, the diuretic activity of furosemide was weaker in the renal hypertensive rat (RHR). Torasemide showed approximately 30 times greater diuretic potency than furosemide. Torasemide and furosemide demonstrated hypotensive action in hypertensive rat models, but not in the normotensive Wistar rat. Especially in the RHR, torasemide exhibited a more potent hypotensive action than furosemide. These results show that the diuretic and antihypertensive activities of torasemide are effective in various rat models of hypertension, while the diuretic activity of furosemide is weak in certain hypertensive rat models. © 1992 Wiley-Liss, Inc.     

Effect of intravenous infusion time on the pharmacokinetics and pharmacodynamics of the same total dose of torasemide in rabbits

The pharmacokinetics and pharmacodynamics of torasemide were evaluated after intravenous administration of the same total dose of torasemide at a dose of 1mg/kg to rabbits with different infusion times, 1 min (treatment I), 30 min (treatment II) and 2 h (treatment III). The loss of water and electrolytes in urine induced by torasemide was immediately replaced with infusion of an equal volume of lactated Ringer's solution. All the pharmacokinetic parameters of torasemide, such as total area under the plasma concentration-time curve from time zero to time infinity (AUC), total body clearance (CL), apparent volume of distribution at steady state (Vss), terminal half-life and mean residence time (MRT), were independent of infusion times. However, the 8 h urine output (235, 534 and 808 ml) and 8 h urinary excretion of sodium (24.2, 80.1 and 89.2 mmol) and chloride (27.1, 89.2 and 94.0 mmol) were significantly greater in treatments II and III than those in treatment I, although the total 8 h urinary excretion of unchanged torasemide (1210, 1210 and 1310 microg) were not significantly different among the three treatments. This could be due to the higher diuretic efficiencies in treatments II and III.     

Urinary Excretion Profile of Torasemide and its Diuretic Action in Dogs

The plasma concentration profile, urinary excretion rate and diuretic response were studied in anaesthetized dogs after an intravenous administration of torasemide or furosemide. The urinary excretion rate of furosemide decreased rapidly after administration. The plasma concentration, which is related to the urinary excretion profile, also decreased rapidly. The diuretic response, which reflected the excretion rate, occurred rapidly after administration but lasted for a short time. The urinary excretion rate of torasemide was much lower than that of furosemide and decreased slowly after administration. The plasma concentration also decreased slowly. The diuretic response to torasemide occurred more slowly but lasted longer than the response to furosemide. These results suggest that the diuretic response profile of either diuretic depends on their urinary excretion rate, and that the difference in the diuretic response between torasemide and furosemide may be explained by the different transfer rate of the drugs from the plasma to the nephron.     

Diuretic profile of a novel loop diuretic torasemide in rats and dogs.

In the present study, the authors have examined the diuretic action of a novel loop diuretic torasemide and compared it to those of other diuretics, employing normal rats and dogs. Oral administration of torasemide elicited a dose-dependent increase in urine volume and electrolyte excretion, and elevated the urinary Na/K ratio in rats. These effects were more potent than those of the other diuretics furosemide, trichlormethiazide, indapamide and spironolactone. Moreover, torasemide exhibited a similar or higher urinary Na/K ratio than the combination of these diuretics and spironolactone. In a study employing anaesthetized dogs, i.v. injection of torasemide resulted in a higher urinary Na/K ratio in comparison to furosemide, in addition to potent and long-lasting diuretic activity.     

Pharmacological properties of the new potent diuretic torasemide in rats and dogs

Torasemide, a pyridine-3-sulfonylurea derivative, has potent diuretic activity in rats and dogs. In both species urinary volume and electrolyte excretion increased linearly with the logarithm of the dose, thus resembling the profile of a high ceiling diuretic. The minimum effective dose by oral route was 0.2 mg/kg in the rat and less that 0.1 mg/kg in the dog. Maximal effect was obtained with about 10 mg/kg. Experiments by oral and i.v. routes in the rat indicated that torasemide was equally potent by both oral and parenteral administration. In both rats and dogs, urinary excretions induced by torasemide were similar to those obtained with furosemide. However, for the same natriuretic effect, potassium losses with torasemide were significantly less than with furosemide. On a weight basis, torasemide was 9-40 times more potent than furosemide in the rat and about 10 times in the dog. After oral administration the diuretic effects of torasemide started within 20 min and lasted approximately 2 h in the rat and more than 8 h in the dog. The activity of torasemide was not decreased after a repeated daily oral dose of 10 mg/kg for 15 days in the rat. Torasemide at a daily oral dose of 5 mg/kg for 12 days effectively reduced the arterial blood pressure in desoxycortone induced hypertension in the rat. Besides the diuretic and antihypertensive effects no other significant pharmacological effects were observed with torasemide in the different in vitro and in vivo experiments. Torasemide was practically fully absorbed by the gastrointestinal tract, its bioavailability by oral route ranged from 80 to 100%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal effects of the high ceiling diuretic torasemide in rats and dogs

The mode of action of torasemide was investigated by clearance experiments in dogs and rats. In the dog, torasemide (1 mg/kg i.v.) had no significant effect on glomerular filtration rate (GFR) but increased p-aminohippuric acid (PAH) clearance by 16% (p less than 0.01). In the rat both GFR and PAH clearance were significantly decreased, on an average 8-17%, by torasemide infused in the dose range of 1 to 20 mg/kg i.v. After i.v. injection the onset of diuresis was observed within 5 to 10 min and peak effect within 20 to 40 min in the rat and within 40 to 60 min in the dog. Fractional water and sodium excretions of nearly 25% were obtained in the rat with a dose of 8 mg/kg i.v. At equipotent doses, torasemide and furosemide induced similar diuretic and natriuretic effects in function of time in the rat. In the dog the effects lasted much longer with torasemide than with furosemide. This difference can be related to the longer half-life (about 8 h) of torasemide in the dog. In both species significant differences could be noted between torasemide and furosemide with respect to the time course of their effects on the urinary excretion of potassium. From the first experimental hour on, torasemide proved to be significantly less kaliuretic than furosemide as shown by increased Na/K ratios, during the third experimental hour they reached 20.5 vs 9.9 in the dog and 11 vs 7.5 in the rat with torasemide and furosemide, respectively. In hydropenic dogs, free water reabsorption was significantly reduced with torasemide and osmolar clearance significantly increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and pharmacodynamics of furosemide after intravenous and oral administration to spontaneously hypertensive rats and DOCA-salt-induced hypertensive rats

The pharmacokinetics and pharmacodynamics of furosemide were investigated after intravenous (i.v.), 1 mg/100 g body weight, and oral administration, 2 mg per 100g body weight, to spontaneously hypertensive rats (SHRs) and deoxycorticosterone acetate-salt-induced hypertensive rats (DOCA-salt rats). After i.v. administration, the 8 h urinary excretion of furosemide/g kidney (397 versus 572 μg) was significantly lower and the non-renal clearance (5.78 versus 3·94 ml min^?1 kg^?1) was significantly faster in SHRs of 16 weeks of age than in age-matched control Wistar rats. This suggested that the nonrenal metabolism of furosemide could be faster in SHRs of 16 weeks of age than in age-matched control Wistar rats, and this could be supported by the significantly greater amount of 4-chloro-5-sulphamoyl anthranilic acid, a metabolite of furosemide, excreted in 8 h urine as expressed in terms of furosemide (11·1 versus 4·79% of the i.v. dose) in SHRs. It could also be supported at least in part by a study of liver homogenate; the amount of furosemide remaining per gram of liver after 30 min incubation of 50μg of furosemide with the 9000g supernatant fraction of liver homogenate was significantly smaller (40·4 versus 43·7μg) in SHRs of 16 weeks of age than in age-matched Wistar rats. The greater metabolic activity of furosemide in liver may also be supported by the result that the amount of hepatic cytochrome P-450 (0·7013 versus 0·5186 nmol/mg protein) and the weights of liver (3·52 versus 2·93% of body weight) were significantly greater in SHRs of 16 weeks of age than in age-matched Wistar rats. After i.v. administration of furosemide, the 8 h urine output (9·93 versus 16·5 ml) and 8 h urinary excretion of sodium (1·21 versus 2·05 mmol) and chloride (1·37 versus 2·17 mmol) per gram of kidney in SHRs of 16 weeks of age were lower than those in age-matched Wistar rats, this could be due to the significantly smaller amount of furosemide excreted in 8 h urine per gram of kidney. After oral administration, the pharmacokinetics and pharmacodynamics of furosemide were not significantly different between SHRs and the control Wistar rats of 16 weeks of age. After i.v. and oral administration of furosemide, there were no significant differences in the pharmacokinetics and pharmacodynamics between DOCA-salt rats and control SD rats of 16 weeks of age except for the significantly lower urinary excretion of potassium per gram of kidney in DOCA-salt rats. On the other hand, the 8 h urinary excretion of furosemide and non-renal clearance were not significantly different between SHRs of six weeks of age and age-matched control Wistar rats after i.v. administration of furosemide. Since the non-renal metabolism of furosemide was not faster in either DOCA-salt rats of 16 weeks of age or SHRs of six weeks of age than that in the respective age-matched control group, the faster non-renal metabolism of furosemide in SHRs of 16 weeks of age could be due to the physiological factor from the chronic phase of hypertension in SHRs, and could not be due solely to the heredity of SHRs or the hypertensive state itself.     

Chronopharmacology of furosemide in rats with amikacin-induced acute renal damage.

To examine the influence of amikacin-induced acute renal damage on the urinary excretion of furosemide and the time-dependent variation in the urinary amount of the agent, amikacin (1.2 g/kg) was given intraperitoneally to Wistar rats. Study I: Three percent b.w. of 1% NaCl solution was given orally before and after amikacin treatment, and an 8-hour urine for N-acetyl-beta-D-glucosaminidase (NAG) was collected. Study II: Furosemide (30 mg/kg) in 3% b.w. of 1% NaCl solution was given orally at 12 a.m. or 12 p.m. before and after amikacin treatment, and an 8-hour urine for sodium and furosemide was collected. Following amikacin treatment, urinary excretion of NAG increased, while urine volume and urinary excretion of sodium and furosemide decreased. Urinary excretion of furosemide and its diuretic effects were significantly greater at 12 a.m. than at 12 p.m. before and after treatment. However the time-dependent differences in these parameters were diminished by amikacin treatment. These results suggest that the urinary excretion of furosemide is reduced and the extents of the time-dependent variation in the urinary furosemide and its diuretic effects are altered in rats with amikacin-induced renal damage.     

Pharmacokinetic and pharmacodynamic changes of furosemide after intravenous and oral administration to rats with alloxan-induced diabetes mellitus

Because some physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics and pharmacodynamics of the drugs to treat the disease, the pharmacokinetics and pharmacodynamics of furosemide were investigated after intravenous (i.v.) and oral administration of the drug (6 mg per whole body weight) to control rats and alloxan-induced diabetes mellitus rats (AIDRs). After i.v. administration, the total body clearance (5.47 versus 7.05 mL min⁻¹ kg⁻¹) was significantly slower in AIDRs and this was due to significantly slower renal clearance (2.35 versus 4.33 mL min⁻¹ kg⁻¹) because the nonrenal clearance was comparable between two groups of rats. The 8 h urinary excretion of furosemide after i.v. administration decreased significantly (2280 versus 3760 μg) in AIDRs due to impaired kidney function; the glomerular filtration rate measured by creatinine clearance was significantly slower (2.86 versus 4.33 mL min⁻¹ kg⁻¹) and both the plasma urea nitrogen (43.5 versus 17.3 mg dL⁻¹) and kidney weight (0.953 versus 0.749% of body weight) increased significantly in AIDRs. This resulted in a significant decrease in the 8 h urine output per g kidney (17.8 versus 43.6 mL) in AIDRs. However, the 8 h diuretic efficiency was not significantly different between two groups of rats. After oral administration, the area under the plasma concentration–time curve from time 0 to 8 h decreased significantly in AIDRs (1200 versus 1910 μg·min mL⁻¹) due to considerably decreased absorption of furosemide from gastrointestinal tract of AIDRs. After oral administration, the 8 h urine output per g kidney (18.6 versus 36.4 mL) also decreased significantly in the AIDRs due to significantly decreased 8 h urinary excretion of furosemide (405 versus 2210 μg), however, the 8 h diuretic efficiency increased significantly (127 versus 35.2 mL mg⁻¹) in AIDRs. © 1998 John Wiley & Sons, Ltd.     

Effects of phenobarbital and 3-methylcholanthrene pretreatment on the pharmacokinetics and pharmacodynamics of furosemide in rats

The effects of pretreatment with the enzyme inducers phenobarbital (PB) and 3-methylcholanthrene (3-MC) on the pharmacokinetic and pharmacodynamic parameters of furosemide were examined in rats. The nonrenal clearance (4.58 versus 6.18 mL/min/kg) increased significantly in PB-treated rats. This suggested that the nonrenal metabolism of furosemide increased by pretreatment with PB. This relationship was supported by the results of a tissue homogenate study; the amounts of furosemide remaining per gram of tissue after 30 min of incubation of 50 micrograms of furosemide with the 9000 x g supernatant fraction of liver, stomach, and kidney tissue homogenates decreased significantly in PB-treated rats. The contents of hepatic cytochrome P-450 (1.29 versus 2.15 nmol/mg protein) and the weights of liver and stomach increased significantly in PB-treated rats, suggesting that the metabolizing enzymes for furosemide are induced by pretreatment with PB. The 8-h urine output per 100 g of body weight increased significantly in PB-treated rats; however, the 8-h urinary excretion of furosemide per 100 g of body weight (797 versus 635 micrograms) decreased significantly in PB-treated rats. Alterations in the urine output might be due to the hormonal alterations in the concentration-effect relationship for furosemide in PB-treated rats. In 3-MC-treated rats, pharmacokinetic and pharmacodynamic parameters of furosemide were not significantly different, indicating that the metabolizing enzymes for furosemide were not induced by pretreatment with 3-MC. However, the contents of hepatic cytochrome P-450 and the weights of liver and stomach increased significantly.     

Urinary Excretion and Diuretic Action of Furosemide in Rats: Increased Response to the Urinary Excretion Rate of Furosemide in Rats with Acute Renal Failure

A urinary excretion–response curve representing the urinary excretion rate of furosemide versus the urinary excretion rate of (Na⁺ + K⁺) was used to analyze furosemide action in rats with uranyl nitrate-induced acute renal failure (ARF) with and without dopamine coadministration. Urinary excretion of furosemide, but not its serum concentration, was the determinant for the diuretic action of furosemide. Increased diuretic response was observed in ARF rats, although the total diuretic response and urinary recovery of furosemide within 2 hr decreased. Dopamine enhanced furosemide-induced diuresis in ARF rats in terms of the total urine output and urinary electrolyte excretion, although the urinary excretion–response curves were not different. This enhancement by dopamine was found to be caused by the augmented urinary excretion of furosemide and the increased response to this drug in ARF rats. These findings suggest the contribution of decreased concentrating ability along the nephron and/or increased sensitivity of cells at the site of action to this drug.     

Effects of water deprivation for 72 hours on the pharmacokinetics of DA-7867, a new oxazolidinone, in rats

The pharmacokinetic parameters of DA-7867 were compared after intravenous and oral administration at a dose of 10 mg/kg in control rats and in rats with water deprivation for 72 h (rat model of dehydration). After intravenous administration in the rat model of dehydration, the Cl(nr) (0.654 versus 0.992 ml/min/kg) and Cl(r) (0.0273 versus 0.0784 ml/min/kg) values were significantly slower than in the controls. The slower Cl(nr) could be due mainly to a significantly smaller total amount of unchanged DA-7867 recovered from the gastrointestinal tract at 24 h (GI(24 h): 5.16% versus 9.21% of intravenous dose) due to impaired liver function in the rat model of dehydration. The slower Cl(r) could be due mainly to a significantly smaller 24 h urinary excretion of unchanged drug (Ae(0-24 h): 4.41% versus 7.75% of intravenous dose) due to urine flow rate-dependent Cl(r) of DA-7867 in the rat model of dehydration. Hence, the Cl was significantly slower in the rat model of dehydration (0.677 versus 1.07 ml/min/kg). After intravenous administration in the rat model of dehydration, the V(ss) of DA-7867 was significantly smaller than in the controls (396 versus 506 ml/kg) due mainly to significantly smaller free (unbound to plasma proteins) fractions of DA-7867 in plasma (6.90% versus 29.2%) in the rat model of dehydration. After oral administration in the rat model of dehydration, the AUC was significantly greater than that in controls (10800 versus 7060 microg min/ml) due mainly to a significantly smaller Ae(0-24 h) than in controls (3.50% and 6.17% of oral dose).     

EFFECTS OF TORASEMIDE ON RENAL HAEMODYNAMICS AND FUNCTION IN ANAESTHETIZED DOGS

1. We examined the effects of torasemide (0.3 and 1 mg/kg i.v.) on renal haemodynamics and function employing renal clearance and stop-flow techniques in anaesthetized dogs and compared these with furosemide (1 and 3 mg/kg i.v.). 2. Torasemide and furosemide did not influence renal haemodynamics, in the renal clearance study, but caused a dose-related and significant increase in urine flow and urinary excretion of sodium and potassium. Torasemide and furosemide increased fractional excretion of sodium in the distal tubules with a relatively small increase in the fractional excretion of lithium (index of sodium excretion at the proximal tubules, FELi). The diuretic profile of torasemide was of long duration, compared with that of furosemide. 3. Torasemide and furosemide inhibited sodium reabsorption at the distal portion of the tubules in the stop-flow study. 4. It is suggested from these results, that the main diuretic site of action of torasemide is the ascending limb of the loop of Henlé.     

Effect of intravenous infusion time on the pharmacokinetics and pharmacodynamics of the same total dose of furosemide

The pharmacokinetics and pharmacodynamics of furosemide were evaluated after intravenous administration of the same total dose of furosemide in different lengths of infusion time (10 s, 30 min, 2 h, and 8 h) to 6 dogs. The fluid loss in urine was immediately replaced volume for volume with intravenous infusion of Lactated Ringer's solution. The pharmacokinetic parameters such as per cent of the dose excreted in urine, total body and renal clearances, and terminal half-life were not significantly different with four different infusion times. The volume of distribution at steady state and mean residence time based on venous data, on the other hand, appeared to increase with increasing infusion time. The mean values for Vss were 0.334, 0.478, 0.499, and 0.708 1 kg-1 for 10 s, 30 min, 2 h, and 8 h of infusion, respectively, and the corresponding values for MRT were 17.5, 22.2, 24.8, and 38.1 min. The diuretic effects (urine output and urinary excretion of sodium) were generally found to increase with increasing infusion times; the total mean 24 h urine outputs were 1102, 1464, 2190, and 3470 ml for 10 s, 30 min, 2 h, and 8 h of infusion, respectively, and the corresponding values for sodium excretion were 170, 175, 272, and 440 mmol. Furosemide plasma concentrations and hourly urinary excretion rates of furosemide, sodium, and potassium during the apparent steady state (between 2 and 8 h) in the 8 h infusion study were fairly constant.     

Comparative effects of torasemide and furosemide in rats with heart failure

It has been reported that torasemide but not furosemide, may block the renin-angiotensin-aldosterone system and therefore it might attenuate myocardial remodeling accompanied by left ventricular (LV) dysfunction. We therefore compared the therapeutic effects of torasemide, a long-acting loop diuretic, and furosemide, a short-acting one, on the progression of LV remodeling in a rat model of chronic heart failure (CHF) after experimental autoimmune myocarditis (EAM). CHF was elicited in Lewis rats by immunization with porcine cardiac myosin. Twenty-eight days after immunization, rats were treated for 28 days with torasemide, furosemide, or vehicle. We investigated the effects on metabolic and neurohumoral parameters, cardiac fibrosis and remodeling in EAM rats. Diuresis was increased dose dependently by both torasemide and furosemide, showed an equipotent natriuretic effect. The urinary potassium excretion was significantly increased with furosemide in comparison to torasemide. Myocardial functional parameters were significantly improved by torasemide. Conversely, these parameters did not change in rats receiving furosemide. Torasemide suppressed LV fibrosis, myocardial protein levels of transforming growth factor-beta1, collagen III, and aldosterone synthase and improved survival rate to the control level, but furosemide did not. Moreover, both pharmacological interventions significantly elevated plasma angiotensin II and decreased atrial natriuretic peptide in a dose-dependent manner. Our results demonstrate that compared with furosemide, torasemide treatment significantly improved survival rate, LV function and ameliorated the progression of cardiac remodeling in rats with CHF after EAM.