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.

Potential causes for reported incomplete (usually 40-60%) and often highly variable (e.g., 11-79%) bioavailability of furosemide in humans were investigated. The drug was found to be fairly stable in gastric fluids and its hepatic first-pass elimination (HFPE) was estimated to be much less than 6% based on published i.v. data. The rat was used as the main model for extensive evaluation. About 4% (n = 4) of dose was recovered unchanged in the GI tract after i.v. injection while about 40% (n = 12) was recovered after a 120-fold (0.05-6 mg) dose range of oral administration. In another study 70% of the oral dose eventually disappearing (presumably due to absorption and first-pass elimination) from the GI tract was estimated to occur in just 20 min. These data indicate an unsaturable, incomplete, site-specific absorption as well as a lack of dissolution-rate-limited absorption at the doses studied. Based on plasma data, oral bioavailability in four rats was only 30%, and the HFPE much less than 10%. After oral administration, 61% of the dose was absorbed and/or metabolized in the GI recovery study. Thus, 20-30% of oral dose in rats must be metabolized in the GI wall during absorption. The metabolic activity of stomach (homogenate) from 5 rats was found to be much (e.g., 5-10.5-fold) greater than those of liver and small intestine. This was also confirmed in preliminary studies with 3 rabbits and 1 dog. Large intersubject variability in enzyme activity was found in rats and rabbits. The phenomenon of a presystemic first-pass effect was also substantiated by urinary excretion data of a metabolite. It is postulated that variable gastric and intestinal first-pass metabolism may be a major factor causing incomplete and irregular absorption of furosemide in humans.

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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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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.

Pharmacokinetic studies of drugs in patients with type I diabetes mellitus were scarce. Moreover, similar and different results for drug pharmacokinetics were obtained between diabetic rats and patients with type I diabetes mellitus. Thus, present experimental rat data should be extrapolated carefully in humans.

The dose-dependent pharmacokinetics of itraconazole after intravenous (10, 20, or 30 mg/kg) and oral (10, 30, or 50 mg/kg) administration and the first-pass effects of itraconazole after intravenous, intraportal, intragastric, and intraduodenal administration at a dose of 10 mg/kg were evaluated in rats. After intravenous administration at a dose of 30 mg/kg, the area under the plasma concentration-time curve from time zero to infinity (AUC 0-ؕ ) was significantly greater than those at 10 and 20 mg/kg (1,090, 1,270, and 1,760 g ⅐ min/ml for 10, 20, and 30 mg/kg, dose-normalized at 10 mg/kg). After oral administration, the AUC 0-ؕ was significantly different for three oral doses (380, 687, and 934 g ⅐ min/ml for 10, 30, and 50 mg/kg, respectively, dosenormalized at 10 mg/kg). The extent of absolute oral bioavailability (F) was 34.9% after an oral dose at 10 mg/kg. The AUC 0-ؕ (or AUC 0-8 h ) values were comparable between intravenous and intraportal administration and between intragastric and intraduodenal administration, suggesting that the hepatic and gastric first-pass effects were almost negligible in rats. However, the AUC 0-8 h values after intraduodenal and intragastric administration were significantly smaller than that after intraportal administration, approximately 30%, suggesting that the intestinal first-pass effect was approximately 70% of that of an oral dose of 10 mg/kg. The low F after oral administration of itraconazole at a dose of 10 mg/kg could be mainly due to the considerable intestinal first-pass effect.The pharmacokinetics of itraconazole after oral administration to humans (10-12), rats (11,22,31), and rabbits, cats, and dogs (11) have been reported; however, data on the pharmacokinetics after intravenous administration to humans (12), dogs (11), and rats (22, 31) are scarce. It has been reported (12) that after oral administration of itraconazole to humans, the values for the area under the plasma concentration-time curve from time zero to infinity (AUC 0-ϱ ) for the drug were dose dependent (increased in proportion to dose increases); 50, 100, and 200 mg by capsule after a meal and 100 and 200 mg by capsule after breakfast. However, the dose-dependent pharmacokinetics of itraconazole after intravenous administration and the first-pass effects of the drug have not been reported. It has been reported (31) that the hepatic first-pass effect of itraconazole was estimated to be 18.5% in rats.The purpose of this paper is to report the dose-dependent pharmacokinetics of itraconazole after intravenous (at doses of 10, 20, and 30 mg/kg) and oral (at doses of 10, 30, and 50 mg/kg) administration to rats and the intestinal first-pass effect of itraconazole after intravenous, intraportal, intragastric, and intraduodenal administration (at a dose of 10 mg/kg) to rats. MATERIALS AND METHODSChemicals. Sporanox intravenous solution (10 mg/ml as itraconazole as a solution in hydroxylpropyl-␤-cyclodextrin [HP-␤-CD], sorbitol, propylene glycol, HCl, NaOH, and water for injection; lot no. 01-D01A-IW), Spor...