Woo H. Yoon

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.

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

The effects of differences in the rate and composition of intravenous fluid replacement for urine loss on the pharmacokinetics and pharmacodynamics of azosemide were evaluated using rabbit as the animal model. Each rabbit received a 4 h constant intravenous infusion of 1 mg kg−1 azosemide with 0% replacement (treatment I, n =4), 50% replacement (treatment II, n =5), and 100% replacement (treatment III, n =5) with lactated Ringers solution, as well as with 100% replacement with 5% dextrose in water (D‐5‐W, treatment IV, n =5). Renal clearance and urinary excretion rate of the drug in treatment III were considerably higher than those in treatments I, II, and IV. In spite of the similarities in kinetic properties, diuretic and/or natriuretic effects of azosemide were markedly different among the four treatments. For example, the mean 8 h urine output values were 98·2, 178, 733, and 237 mL for treatments I–IV, respectively, and the corresponding values for sodium excretion were 11·1, 19·4, 76·4, and 14·2 mmol, and for chloride 13·4, 23·8, 78·9, and 17·1 mmol. Except for treatment III, diuresis and/or natriuresis were found to be time dependent, generally decreasing with time until reaching a low plateau during the later hours of infusion. The present findings also show that (i) no fluid replacement and 100% replacement with D‐5‐W both produce the same degree (not significantly different) of severe acute tolerance in natriuresis, indicating the insignificance of water compensation in tolerance development; (ii) in treatment II, where neutral sodium balance was achieved, the development of acute tolerance in diuresis can mainly be attributed to negative water balance under this special condition; and (iii) at steady state the hourly diuresis and natriuresis can differ up to about 6·87‐ and 5·21‐fold between treatments. Some implications for the bioequivalence evaluation of dosage forms of azosemide are discussed.

Pharmacokinetic and pharmacodynamic changes of azosemide after intravenous and oral administration of azosemide to uranyl nitrate-induced acute renal failure rats.

The pharmacokinetic and pharmacodynamic differences of azosemide were investigated after intravenous (IV) and oral administration of azosemide, 10 mg kg−1, to the control and uranyl nitrate‐induced acute renal failure (U‐ARF) rats. After IV administration, the plasma concentrations of azosemide were significantly higher in the U‐ARF rats and this resulted in a significant increase in AUC (2520 versus 3680 μg min mL−1) and significant decrease in Cl (3.96 versus 2.72 mL min−1 kg−1) of azosemide. The significant decrease in Cl in the U‐ARF rats was due to the significant decrease in Clr of azosemide (1.55 versus 0.00913 mL min−1 kg−1) due to the decrease in kidney function in the U‐ARF rats. After IV administration, the urine output (38.5 versus 8.45 mL 100 g−1 body weight) and urinary excretion of sodium (4.60 versus 0.420 mmol 100 g−1 body weight) decreased significantly in the U‐ARF rats. After oral administration, the AUC0–8 h of azosemide decreased significantly (215 versus 135 μg min mL−1) in the U‐ARF rats possibly due to the decreased GI absorption of azosemide. After oral administration, the 24‐h urine output decreased considerably (16.1 versus 11.2 mL 100 g−1 body weight, p <0.098) and the 24‐h urinary excretion of sodium (1.74 versus 0.777 mmol 100 g−1 body weight) decreased significantly in the U‐ARF rats. The IV and oral doses of azosemide needed to be modified in the acute renal failure patients if the present rat data could be extrapolated to humans.

THE EFFECT OF INTRAVENOUS INFUSION TIME ON THE PHARMACOKINETICS AND PHARMACODYNAMICS OF THE SAME TOTAL DOSE OF AZOSEMIDE 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 Ringers 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 8h urine output (235, 534 and 808 ml) and 8h 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 µg) were not significantly different among the three treatments. This could be due to the higher diuretic efficiencies in treatments II and III. Copyright

Pharkacokinetics and pharmacodynamics of furosemide after direct administration into the stomach or duodenum

The pharmacokinetics and pharmacodynamics of furosemide were compared after an oral administration or a direct administration of Lasix into the duodenum in humans (40 mg). Furosemide was absorbed quickly after a direct administration of Lasix into the duodenum; the peak plasma concentration of furosemide was reached within 1 h in both routes of administration, and the peak concentration was higher in all four subjects after a direct administration into the duodenum than after an oral administration. Furosemide was absorbed considerably after a direct administration of Lasix into the duodenum; the values of the area under the plasma concentration–time curves of furosemide from time zero to 4 h (AUC0–4 h, 93·6 versus 122 μg min mL−1, p <0·123) and the cumulative amounts of the dose excreted in 8 h (10 600 versus 15 000 μg, p <0·0185) and 24 h (11 300 versus 15 400 μg, p <0·0192) urine as unchanged furosemide were significantly higher after a direct administration into the duodenum than after an oral administration. However, the amounts excreted in urine as glucuronide conjugates, a metabolite of furosemide, tended to increase after an oral administration (4030 versus 1670 μg as expressed in terms of furosemide, p <0·0858) when compared to a direct administration into the duodenum, possibly due to the increased gastric first‐pass metabolism of furosemide. The 8 h urine output and 8 h urinary excretion of sodium did not increase significantly after a direct administration of Lasix into the duodenum, despite the significantly greater amount of the drug delivered to the active site after a direct administration into the duodenum. This could be explained by the fact that the urinary excretion rates of furosemide after a direct administration into the stomach were closer to the values of maximally efficient urinary excretion rate of furosemide during the 8 h experimental period than after a direct administration into the duodenum.

Pharmacokinetics, tissue distribution and biliary excretion of FT-ADM after intravenous administration of DA-125, a prodrug of FT-ADM to dogs. A new adriamycin analog containing fluorine

Abstract The pharmacokinetic parameters, tissue distribution and biliary excretion of M1-M4 were estimated after intravenous (i.v.) administration of DA-125, 2.5 mg per kg to beagle dogs. The mean values of the terminal half-life, mean residence time, total body clearance and apparent volume of distribution at steady state of M1 were 266 min, 170 min, 61.3 ml min −1 kg −1 and 9500 ml kg −1 , respectively (four male and four female dogs). M1 was highly concentrated in lung (five male and five female dogs), and this probably means that lung tumors are subjected to greater exposure to M1, an active metabolite of DA-125. The 8 h biliary excretion of M2 was significantly greater than that of M1, 53.6 vs 6860 μg (three male and two female dogs). The amount of glucuronide and/or sulfate conjugates of M1-M4 in the bile sample was negligible.

Pharmacokinetics and Pharmacodynamics of Azosemide after Intravenous and Oral Administration to Rats with Alloxan-induced Diabetes Mellitus

Because physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics and pharmacodynamics of the drugs used to treat the disease, the pharmacokinetics and pharmacodynamics of azosemide were investigated after intravenous and oral administration of the drug (10 mg kg−1) to control and alloxan‐induced diabetes mellitus rats (AIDRs).

Effects of water deprivation for 48 hours on the pharmacokinetics and pharmacodynamics of furosemide in rats

The effects of water deprivation for 48 h on the pharmacokinetics and pharmacodynamics of furosemide were examined after intravenous, 8 mg/kg body weight, and oral administration, 16 mg/kg body weight, of furosemide to control and water deprived rats. After i.v. administration, the total body and nonrenal clearances decreased significantly in water–deprived rats. The urine output, urinary excretion of sodium, potassium and chloride based on grams of kidney weight, and the diuretic, natriuretic and chloruretic efficiencies decreased significantly in waterdeprived rats after both intravenous and oral administration of furosemide, suggesting that the dose of furosemide for water–deprived patients may require modification.

Pharmacokinetics of ciprofloxacin after intravenous administration of ciprofloxacin-TOF in rabbits

Abstract The pharmacokinetic parameters and tissue distribution of ciprofloxacin were compared after intravenous (i.v.) administration of ciprofloxacin-HCl or ciprofloxacin-TOF salts, 30 mg kg −1 as free ciprofloxacin to rabbits. The pharmacokinetic parameters and tissue distribution of ciprofloxacin were not significantly different between i.v. administration of ciprofloxacin-TOF and ciprofloxacin-HCl salts, indicating that ciprofloxacin-TOF salt is pharmacokinetically equivalent to ciprofloxacin-HCl salt. Radioactivity was evenly distributed in all the tissues (or organs) studied at 48 h after i.v. administration of 1- 14 C- or 1,2,3,4,5- 14 C-labelled TOF, 750000 dpm kg −1 to rabbits and the mean percentages of i.v. dose excreted in 48 h urine as measured radioactivity were 23.6 and 26.1% for [1- 14 C]- and [1,2,3,4,5- 14 C]TOF, respectively.