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  • 1
    Electronic Resource
    Electronic Resource
    UrinarypH and urine flow independent renal clearance of methotrexate in dogs (1985)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 13 (1985), S. 159-171 
    Details
    ISSN: 1573-8744
    Keywords: methotrexate renal clearance ; urine pH and flow independent ; plasma concentration dependent
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The effects of urine flow and pH on methotrexate renal clearance were studied in seven conditioned male Beagle-Mongrel dogs. Steady-state plasma methotrexate and inulin concentrations were achieved by i.v. infusions preceded by i.v. bolus doses. Plasma and urine concentrations of methotrexate were quantitated by a sensitive high-performance liquid Chromatographic assay, while those of inulin were measured by a colorimetric method. Since plasma protein binding of methotrexate was pH and concentration independent, methotrexate/inulin renal clearance without correcting for plasma binding was used for most of the data analyses. The results showed that the renal clearance ratios at the plasma methotrexate levels (approximately 0.1, 1.0, 20.0, and 100 μg/ml) studied remained relatively constant when urine pH (differences of up to about 2.5 units) and flow rate (differences of up to approximately 30 times) were changed. This indicated that renal reabsorption of methotrexate in these dogs was negligible. However, concentration-dependent renal clearance was observed. The mean renal clearances were 3.84, 3.94, 2.73, and 2.72 ml/min/kg at plasma concentrations of about 0.1, 1.0, 20.0, and 100.0 μg/ml, respectively, when urine was alkalized by sodium bicarbonate. The corresponding clearances were 4.02, 4.28, 2.62, and 2.65 ml/min/kg when urine was acidified by ammonium chloride. These showed the existence of saturable tubular secretion of methotrexate. No 7-hydroxy-methotrexate, a metabolite found in other species, was detected in the urine and plasma of the dogs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059396
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  • 2
    Electronic Resource
    Electronic Resource
    Concentration andpH dependent steady-state volume of distribution of methotrexate estimated by a simple physiologically based method (1984)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 12 (1984), S. 597-610 
    Details
    ISSN: 1573-8744
    Keywords: pharmacokinetics ; steady-state volume of distribution ; methotrexate pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The effects of plasma concentration and pH on the steady-state volume of distribution, Vss,of methotrexate (MTX) were studied in five conditioned male beagle-mongrel dogs. Steady-state plasma MTX concentrations of approximately 1, 20, and 100μg/ml were targeted for by i.v. bolus doses followed by i.v. infusions. An isotonic solution of sodium bicarbonate or ammonium chloride was simultaneously infused for the purpose of inducing plasma pH change, while the infusion of an isotonic solution of sodium chloride served as a control. Plasma and urine concentrations of MTX were quantitated by a sensitive high-performance liquid chromatographic method, and the Vss of MTX was estimated by a recently reported physiologically based method of Chiou and Lam. Statistically significant (p〈0.05) concentration and plasma pHdependent Vss of MTX were observed. Concentration dependence of Vss was noted in sodium chloride and ammonium chloride infused dogs, but not in bicarbonate treated dogs. There was an average 50.0 and 44.8% increase in Vss at 1 μg/ ml relative to the two higher concentrations (20 and 100 μg/ ml) for dogs treated with ammonium and sodium chloride, respectively. However, Vss of MTX at the targeted concentrations of 20 and 100 μg/ml was relatively constant. Plasma pHdependence of Vss was observed only at the plasma concentration of 1 μg/ml, and on the average, ammonium chloride and sodium chloride treatments resulted in 50.0 and 31.3% higher Vss,respectively, when compared with the bicarbonate treatment. These phenomena appear to be adequately explained by the reported tissue uptake kinetics of MTX.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059555
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  • 3
    Electronic Resource
    Electronic Resource
    The phenomenon and cause of the dose-dependent oral absorption of chlorothiazide in rats: Extrapolation to human data based on the body surface area concept (1987)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 15 (1987), S. 369-386 
    Details
    ISSN: 1573-8744
    Keywords: dose-dependent oral absorption ; chlorothiazide ; intestinal absorption ; body surface area ; interspecies correlation in pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The reported incomplete and dose-dependent absorption of chlorothiazide in humans was demonstrated in six rats after five oral solutions at doses of 0.93, 2.55, 9.23, 25.6, and 70.2 mg/kg. Mean 48-hr urinary recoveries of intact drug were 57.3, 50.4, 36.7, 22.8, and 15.3%, respectively. A similar degree of dose dependency in absorption was found in rat, dog, and human when the doses were related to unit body surface area (BSA) but not on unit body weight, indicating similar interspecies absorptive capacity in terms of unit BSA. This finding may be partly rationalized by marked similarities in the reported solution transit time (2–3 hr) in the small intestine as well as in the calculated gross surface area of the small intestine per unit BSA (0.163 for rat and 0.132 for human). Contrary to the previous postulation of a specific absorption site, the drug was absorbed from different regions of the GI tract with apparent 1-hr absorption rates, studied by the in situclosed-loop method, in the following rank order: jejunum (34.6%)〉 duodenum (32.7%)〉 large intestine (20.1%)〉ileum (18.0%) 〉 stomach (12.4%). Different from the commonly assumed first-order absorption process, the intestinal loop absorption was concentration-dependent, suggesting a saturable mechanism. For example, the absorption rate at 0.008 mg/mL was higher than that at 0.2mg/mL in Heal loops (61%, p〈0.01) and jejunal loops (22%, p〈0.1). In addition, the absorption rates at pH 6 and 7.4 were statistically identical, indicating a lack of ionization effect that is important in the passive absorption process. The solubility-limited absorption could probably be ruled out at doses below 2.55 mg/kg for rat and 125 mg for human in view of higher aqueous solubilities at 37
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01066519
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  • 4
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of bumetanide after intravenous and oral administration to rats: Absorption from various GI segments (1994)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 1-17 
    Details
    ISSN: 1573-8744
    Keywords: bumetanide ; pharmacokinetics ; pharmacodynamics ; multiple peaks ; absorption from various GI segments
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Bumetanide, 2, 8, and 20 mg/kg, was administered both intravenously and orally to determine the pharmacokinetics and pharmacodynamics of bumetanide in rats (n=10–12). The absorption of bumetanide from various segments of GI tract and the reasons for the appearance of multiple peaks in plasma concentrations of bumetanide after oral administration were also investigated. After iv dose, the pharmacokinetic parameters of bumetanide, such ast 1/2 (21.4, 53.8 vs. 127 min),CL (35.8, 19.1 vs. 13.4 ml/min per kg),CL NR (35.2, 17.8 vs. 12.6 ml/min per kg) andV SS (392, 250 vs. 274 ml/kg) were dose-dependent at the dose range studied. It may be due to the saturable metabolism of bumetanide in rats. After iv dose, 8-hr urine output per 100g body weight increased significantly with increasing doses and it could be due to significantly increased amounts of bumetanide exreted in 8-hr urine with increasing doses. The total amount of sodium and chloride exreted in 8-hr urine per 100g body weight also increased significantly after iv dose of 8 mg/kg, however, the corresponding values for potassium were dose-independent. After oral administration, the percentages of the dose excreted in 24-hr urine as unchanged bumetanide were dose-independent. Bumetanide was absorbed from all regions of GI tract studied and approximately 43.7, 50.0, and 38.4% of the orally administered dose were absorbed between 1 and 24 hr after oral doses of 2, 8, and 20 mg/kg, respectively. Therefore, the appearance of multiple peaks after oral administration could be mainly due to the gastric emptying patterns. The percentages of bumetanide absorbed from GI tract as unchanged bumetanide for up to 24 hr after oral doses of 2, 8, and 20 mg/kg (96.2, 95.4 vs. 98.2%) were not significantly different, suggesting that the problem of precipitation of bumetanide in acidic gastric juices or dissolution may not contribute significantly to the absorption of bumetanide after oral administration. Urine output per 100g body wt increased at oral doses of 8 and 20 mg/kg.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02353407
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  • 5
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of azosemide after intravenous and oral administration to rats: Absorption from various GI segments (1996)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 24 (1996), S. 551-568 
    Details
    ISSN: 1573-8744
    Keywords: azosemide ; pharmacokinetics ; pharmacodynamics ; multiple peaks ; absorption from various segments of GI tract
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Azosemide, 5, 10, 20, and 30 mg/kg, was administered both intravenously and orally to determine the pharmacokinetics and pharmacodynamics of azosemide in rats (n=7–12). The absorption of azosemide from various segments of GI tract and the reasons for the appearance of multiple peaks in plasma concentrations of azosemide after oral administration were also investigated. After intravenous (iv) dose, the pharmacokinetic parameters of azosemide such ast 1/2, MRT, VSS, CL, CLR, and CLNR were found to be dose-dependent in the dose ranges studied. The percentages of the iv dose excreted in 8-hr urine as azosemide, MI (a metabolite of azosemide), glucuronide of azosemide, and glucuronide of MI—expressed in terms of azosemide—were also dose-dependent in the dose ranges studied. The data above suggest saturable metabolism of azosemide in rats. The measurements taken after the iv administrations such as the 8 hr urine output, the total amount of sodium and chloride excreted in 8-hr urine per 100 g body weight, and diuretic, natriuretic, kaluretic, and chloruretic efficiencies were also shown to be dose-dependent. However, the total amount of potassium excreted in 8-hr urine per 100 g body weight was dose-independent. Similar dose-dependency was also observed following oral administration. Azosemide was absorbed from all regions of GI tract studied and approximately 93.5, 79.1, 86.1, and 71.5% of the doses (5, 10, 20, and 30 mg/kg, respectively) were absorbed between 1 and 24 hr after oral administration. The appearance of multiple peaks after oral administration is suspected to be due mainly to the gastric emptying pattern. The percentages of azosemide absorbed from the GI tract as unchanged azosemide for up to 24 hr after oral doses of 5, 10, 20, and 30 mg/kg were significantly different with doses (decreased with increasing doses), suggesting that the problem of azosemide precipitating in acidic gastric juices or dissolution may have at least partially influenced the absorption of azosemide after oral administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02353480
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  • 6
    Electronic Resource
    Electronic Resource
    Evaluation of potential causes for the incomplete bioavailability of furosemide: Gastric first-pass metabolism (1983)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 623-640 
    Details
    ISSN: 1573-8744
    Keywords: bioavailability of furosemide ; GI wall first-pass metabolism ; incomplete absorption ; unsaturable site-specific GI absorption ; hepatic first-pass metabolism ; chemical degradation ; precipitation in GI tract
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract 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 〈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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059061
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  • 7
    Electronic Resource
    Electronic Resource
    Effects of the rate and composition of fluid replacement on the pharmacokinetics and pharmacodynamics of intravenous furosemide (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 495-509 
    Details
    ISSN: 1573-8744
    Keywords: furosemide ; pharmacokinetics ; pharmacodynamics ; fluid replacement
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Effects of differences in the rate and composition of intravenous fluid replacement for urine loss on the pharmacokinetics and pharmacodynamics of furosemide were evaluated using the dog as a model animal. Each of six dogs received 8-hr constant intravenous infusion of 20 mg (15 mg used in one dog) of furosemide with 0% replacement (treatment I), 50% replacement (treatment II), and 100% replacement (treatment III) with lactated Ringer's solution, as well as with 100% replacement with 5% dextrose in water (treatment IV). Most pharmacokinetic parameters, such as plasma clearance, steady-state volume of distribution, mean residence time, and terminal half-life, were essentially the same in all four treatments. Renal clearances and urinary excretion rates of the drug in treatments II–IVwere essentially the same, but about 20% higher than those in treatment I.In spite of the similarities in kinetic properties, diuretic and/or natriuretic effects from furosemide were markedly different among the four treatments. For example, mean 10-hr urine outputs were 646, 1046, 3156, and 1976 ml and mean 10-hr sodium excretions were 87.0, 142, 383, and 97.2 mmole for treatments I–IV,respectively. Except for treatment III,diuresis and/or natriuresis were found to be time-dependent, generally decreasing with time until reaching a low plateau during later hours of infusion. The present findings also showed that (1)no fluid replacement and 100% replacement with 5% dextrose solution both produced the same degree of severe acute tolerance in natriuresis, indicating the insignificance of water compensation in tolerance development; (2)in treatment II,where neutral sodium balance was achieved, the development of acute tolerance in diuresis and natriuresis can mainly be attributed to negative water balance under this special condition; (3)at steady state the hourly diuresis and natriuresis could differ up to about ten times between treatments. Some implications for the kinetic/dynamic relationship or modeling, in the clinical use, and in the bioequivalence evaluation of dosage forms are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059657
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  • 8
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of furosemide in protein-calorie malnutrition (1993)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 21 (1993), S. 1-17 
    Details
    ISSN: 1573-8744
    Keywords: furosemide ; protein-calorie malnutrition ; pharmacokinetics ; pharmacodynamics ; decreased gastric and liver first-pass metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The influence of dietary protein deficiency on pharmacokinetics and pharmacodynamics of furosemide was investigated after iv 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 iv administration, the mean values of CL R , V ss, 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, CL NR 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 iv 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, kaluretic, and chloruretic efficiencies reduced significantly in PCM rats after iv 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 μg of furosemide with the 9000 × gsupernatant fraction of stomach (42.4 vs. 47.9 μg) and liver (41.4 vs. 45.9 μg) 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061772
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