Pharmacodynamics Of Bumetanide Research Articles

Contribution of Monocarboxylate Transporter 6 to the Pharmacokinetics and Pharmacodynamics of Bumetanide in Mice

Bumetanide, a sulfamyl loop diuretic, is used for the treatment of edema in association with congestive heart failure. Being a polar, anionic compound at physiologic pH, bumetanide uptake and efflux into different tissues is largely transporter-mediated. Of note, organic anion transporters (SLC22A) have been extensively studied in terms of their importance in transporting bumetanide to its primary site of action in the kidney. The contribution of one of the less-studied bumetanide transporters, monocarboxylate transporter 6 (MCT6; SLC16A5), to bumetanide pharmacokinetics (PK) and pharmacodynamics (PD) has yet to be characterized. The affinity of bumetanide for murine Mct6 was evaluated using Mct6-transfected Xenopus laevis oocytes. Furthermore, bumetanide was intravenously and orally administered to wild-type mice (Mct6+/+) and homozygous Mct6 knockout mice (Mct6-/-) to elucidate the contribution of Mct6 to bumetanide PK/PD in vivo. We demonstrated that murine Mct6 transports bumetanide at a similar affinity compared with human MCT6 (78 and 84 μM, respectively, at pH 7.4). After bumetanide administration, there were no significant differences in plasma PK. Additionally, diuresis was significantly decreased by ∼55% after intravenous bumetanide administration in Mct6-/- mice. Kidney cortex concentrations of bumetanide were decreased, suggesting decreased Mct6-mediated bumetanide transport to its site of action in the kidney. Overall, these results suggest that Mct6 does not play a major role in the plasma PK of bumetanide in mice; however, it significantly contributes to bumetanide's pharmacodynamics due to changes in kidney concentrations. SIGNIFICANCE STATEMENT: Previous evidence suggested that MCT6 transports bumetanide in vitro; however, no studies to date have evaluated the in vivo contribution of this transporter. In vitro studies indicated that mouse and human MCT6 transport bumetanide with similar affinities. Using Mct6 knockout mice, we demonstrated that murine Mct6 does not play a major role in the plasma pharmacokinetics of bumetanide; however, the pharmacodynamic effect of diuresis was attenuated in the knockout mice, likely because of the decreased bumetanide concentrations in the kidney.

Quercetin, Morin, Luteolin, and Phloretin Are Dietary Flavonoid Inhibitors of Monocarboxylate Transporter 6.

Monocarboxylate transporter 6 (MCT6; SLC16A5) has been recognized for its role as a xenobiotic transporter, with characterized substrates probenecid, bumetanide, and nateglinide. To date, the impact of commonly ingested dietary compounds on MCT6 function has not been investigated, and therefore, the objective of this study was to evaluate a variety of flavonoids for their potential MCT6-specific interactions. Flavonoids are a large group of polyphenolic phytochemicals found in commonly consumed plant-based products that have been recognized for their dietary health benefits. The uptake of bumetanide in human MCT6 gene-transfected Xenopus laevis oocytes was significantly decreased in the presence of a variety of flavonoids (e.g., quercetin, luteolin, phloretin, and morin), but was not significantly affected by flavonoid glycosides (e.g., naringin, rutin, phlorizin). The IC50 values of quercetin, phloretin, and morin were determined to be 25.3 ± 3.36, 17.3 ± 2.37, and 33.1 ± 3.29 μM, respectively. The mechanism of inhibition of phloretin was reversible and competitive, with a Ki value of 22.8 μM. Furthermore, typical MCT substrates were also investigated for their potential interactions with MCT6. Substrates of MCTs 1, 2, 4, 8, and 10 did not cause any significant decrease in MCT6-mediated bumetanide uptake, suggesting that MCT6 has distinct compound selectivity. In summary, these results suggest that dietary aglycon flavonoids may significantly alter the pharmacokinetics and pharmacodynamics of bumetanide and other MCT6-specific substrates, and may represent potential substrates for MCT6.

Effects of the Rate and Composition of Fluid Replacement on Pharmacokinetics and Pharmacodynamics of Intravenous Bumetanide

The effects of differences in the rate and composition of intravenous (iv) fluid replacement for urine loss on the pharmacokinetics and pharmacodynamics of bumetanide were evaluated with rabbit as the animal model. Each rabbit received a 4‐h constant iv infusion of bumetanide at 1 mg/kg with 0% replacement (treatment I, n = 8), 50% replacement (treatment II, n = 6), and 100% replacement (treatment III, n = 7) with lactated Ringer's solution, in addition, another group of rabbits received 100% replacement with 5% dextrose in water (D‐5‐W, treatment IV, n = 4). Some pharmacokinetic parameters, such as the apparent volume of distribution at steady‐state, mean residence time, and terminal half‐life, remained relatively unchanged in all four treatments. Renal clearance and urinary excretion rate of the drug in treatments I–III were essentially the same, but were considerably higher than those in treatment IV. In spite of the similarities in kinetic properties (˜40% difference between lowest and highest values), the diuretic and/or natriuretic effects of bumetanide were markedly different among the four treatments. For example, the mean 8‐h urine output values were 189, 317, 2170, and 306 mL for treatments I–IV, respectively, the corresponding 8‐h sodium excretion values were 9.19, 16.5, 88.8, and 15.7 mmol, and the chloride excretion values were 10.8, 33.7, 77.4, and 11.7 mmol. Except for treatment III, diuresis and/or natriuresis were time dependent, generally decreasing with time until reaching a low plateau during later hours of infusion. The present findings also showed that (1no fluid replacement and 100% replacement with D‐5‐W both produced the same degree not significantly different) 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 can mainly be attributed to negative water balance under this special condition; and (3) at steady state, the hourly diuresis and natriuresis could differ up to ˜10 times between treatments. Some implication for the bioequivalence evaluation of dosage forms of bumetanide is discussed.s

Pharmacokinetics and pharmacodynamics of bumetanide after intravenous and oral administration to rats: Absorption from various GI segments

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 i.v. dose, the pharmacokinetic parameters of bumetanide, such as t1/2 (21.4, 53.8 vs. 127 min), CL (35.8, 19.1 vs. 13.4 ml/min per kg), CLNR (35.2, 17.8 vs. 12.6 ml/min per kg) and VSS (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 i.v. dose, 8-hr urine output per 100 g body weight increased significantly with increasing doses and it could be due to significantly increased amounts of bumetanide excreted in 8-hr urine with increasing doses. The total amount of sodium and chloride excreted in 8-hr urine per 100 g body weight also increased significantly after i.v. 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of water deprivation on the pharmacokinetics and pharmacodynamics of bumetanide in rats

The effects of temporary water deprivation for 48 h on the pharmacokinetics and pharmacodynamics of bumetanide were examined after intravenous (i.v.) administration of bumetanide, 8 mg kg-1 to control and water deprived rats (n = 7). The values of AUC, t1/2 and MRT increased 79.0, 417, and 633 per cent, respectively, and CL and CLNR decreased 44.0 and 41.2 per cent, respectively, in water deprived rats. They were all significantly different. The decreased CLNR in water deprived rats could be due to decreased nonrenal metabolism of bumetanide; it could be supported that the amounts of glucuronide conjugate of bumetanide (52.5 vs 12.9 micrograms), desbutylbumetanide (170 vs 113 micrograms) and its glucuronide conjugation (191 vs 125 micrograms), and sum of the three metabolites (414 vs 229 micrograms), which are expressed in terms of bumetanide excreted in 24 h urine, decreased significantly in water deprived rats. The 8-h urine outputs per 100 g body weight (4.32 vs 1.34 ml) also reduced significantly in water deprived rats, and it might be due to significantly reduced amounts of bumetanide excreted in 8 h urine (90.9 vs 25.7 micrograms) and/or reduced kidney function in water deprived rats. The kidney function based on CLIot (9.87 vs 2.14 ml min-1 kg-1) reduced significantly in water deprived rats. The 8-h urinary excretions of sodium (0.430 vs 0.0818 mmol), potassium (0.567 vs 0.270 mmol), and chloride (0.549 vs 0.0624 mmol) per 100 g body weight also reduced significantly in water deprived rats.

Influence of Protein and Calorie Malnutrition on the Pharmacokinetics and Pharmacodynamics of Bumetanide in Rats

Bumetanide is a loop diuretic that is used for the treatment of edema and hypertension. The rapidly developing syndrome of extracellular fluid overload in some malnourished children has been successfully treated with furosemide, another loop diuretic, and digoxin; however, similar studies with bumetanide have not been conducted to date. Therefore, in the present study, the influence of dietary protein deficiency on the pharmacokinetics and pharmacodynamics of bumetanide was investigated after intravenous (iv) bolus and oral administration of bumetanide to male Sprague-Dawley rats fed on 23% (control rats) or 5% [protein and calorie malnutrition (PCM) rats] protein diet ad libitum for 4 weeks. After an iv dose of bumetanide, 1 mg/100 g body weight, the mean values of renal clearance and percentages of dose excreted as unchanged bumetanide in an 8-h urine sample were 166 and 154% higher, respectively, in PCM than control rats; however, nonrenal clearance (CLNR) was 28% lower. The decrease in nonrenal clearance in PCM rats might be because of the decrease in nonrenal metabolism of bumetanide in PCM rats. The urine output per 100 g of body weight was not significantly different between the two groups of rats after iv administration, although the amount of bumetanide excreted in the 8-h urine sample per 100 g body weight increased significantly in PCM rats. These results could be explained by the fact that the dose of bumetanide used results in urinary excretion rate of bumetanide at the plateau of the concentration-effect relationship. The amounts of sodium, potassium, and chloride excreted in the 8-h urine sample per 100 g body weight were not significantly different between the control and PCM rats after iv administration. Therefore, the diuretic, natriuretic, kaluretic, and chloru- retic efficiencies were significantly reduced in PCM rats after iv administration. After an oral dose of bumetanide at 2 mg/100 g body weight, the extent of bioavailability increased considerably from 21.3 to 36.9% in PCM rats, probably as a result of decreased hepatic first-pass metabolism. The increase in bioavailability in PCM rats may be supported by the results of liver homogenate study; the amount of bumetanide remaining per gram of liver after 30 min of incubation of 100 /μg of bumetanide with the 9000 x g supernatant fraction of the liver homogenate increased significantly (85.5 versus 102 /μg) in PCM rats. The 8-h urine output, and amounts of sodium, potassium, and chloride excreted in the 8-h urine sample per 100 g body weight increased significantly in PCM rats after oral administration as a result of significantly increased amounts of bumetanide excreted in the 8-h urine sample. However, the diuretic, natriuretic, kaluretic, and chloruretic efficiencies were significantly reduced in PCM rats.

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

The pharmacokinetics and pharmacodynamics of bumetanide were evaluated after intravenous (i.v.) administration of the same total dose of bumetanide in different lengths of infusion times, 10 s (treatment I), 1 h (treatment II), and 4 h (treatment III) to rabbits. The fluid loss in urine was immediately replaced volume for volume with i.v. infusion of lactated Ringer's solution. Some pharmacokinetic parameters of bumetanide were infusion time-dependent and it might be due to the saturable metabolism of bumetanide. For example, the mean values of CL (13.6, 25.3 vs 18.2 ml min-1 kg-1), MRT (9.70, 10.6 vs 21.8 min), Vss (128, 217 vs 378 ml kg-1), and CLNR (2.71, 9.24 vs 6.44 ml min-1 kg-1) increased when the same dose of bumetanide was infused in 1 h or 4 h. However, the mean values of t1/2, and CLR were not significantly different among three treatments. The diuretic effects (urine outputs and urinary excretions of sodium and chloride) increased significantly in 1 and 4 h of infusion although the total amounts of urinary excretion of unchanged bumetanide were 21.8 and 20.5 per cent lower in treatments II and III, respectively, when compared with the value in treatment I; the mean values of 8-h urine outputs were 373, 922, and 1030 ml for 10s, 1 h, and 4 h of infusion, respectively, and the corresponding values for 24-h sodium excretions were 49.0, 82.8, and 121 mmol, and for chloride were 47.5, 71.1, and 114 mmol. It could be due to the higher diuretic efficiencies in treatments II and III. Plasma concentrations of bumetanide, and hourly urine outputs and hourly urinary excretion rates of bumetanide, sodium, potassium, and chloride during the apparent steady state (between 1 and 4 h) in the 4 h infusion study were fairly constant.

Pharmacokinetics and pharmacodynamics of bumetanide in neonates treated with extracorporeal membrane oxygenation

Eleven term neonates treated with extracorporeal membrane oxygenation received bumetanide to treat volume overload. All patients had stable renal function, no history of prior diuretic therapy, and no overt evidence of hepatobiliary disease or hypoalbuminemia. Pretreatment creatinine clearance was 35.2 +/- 4.5 ml/min per 1.73 m2 (range, 20.3 to 57.5). Bumetanide, 0.095 +/- 0.003 mg/kg, was administered for 2 minutes into the postmembrane side of the extracorporeal membrane oxygenation circuit. Serial plasma and urine samples were collected for measurement of bumetanide and electrolyte concentrations. Total plasma and renal clearances for bumetanide were 0.63 +/- 0.11 and 0.16 +/- 0.04 ml/min per kilogram, respectively. The steady-state volume of distribution (0.44 +/- 0.03 L/kg) and the elimination half-life (13.2 +/- 3.8 hours) were greater than similar values reported in previous studies of bumetanide disposition in premature and term neonates who were not treated with extracorporeal membrane oxygenation. At observed rates of bumetanide excretion, the diuretic, natriuretic, and kaliuretic responses were linear. Significant diuresis, natriuresis, and kaliuresis were observed, although the duration of these effects was less than expected given the prolonged renal elimination of bumetanide. Nonrenal elimination of bumetanide was variable (47.2% to 96.9%) but higher than expected; this may explain the relatively brief diuretic and kaliuretic response.

Effects of phenobarbital and 3‐methylcholanthrene pretreatment on the pharmacokinetics and the pharmacodynamics of bumetanide in rats

The effects of pretreatment with the enzyme inducers, phenobarbital (PB) and 3-methylcholanthrene (3-MC), on the pharmacokinetic and pharmacodynamic parameters of bumetanide were examined in rats. The nonrenal clearance (19.3 vs 29.6 ml min-1 per kg) of bumetanide increased significantly in PB treated rats. This suggested that the nonrenal metabolism of bumetanide is increased by pretreatment with PB, which was supported by significantly increased amounts of bumetanide glucuronide and desbutyl bumetanide excreted in 8-h urine, and reduced amounts of bumetanide remaining per gram of tissue after 30-min incubation of 100 micrograms of bumetanide with the 9000 xg supernatant fraction of liver, stomach, and kidney tissue homogenates in PB treated rats. The contents of hepatic cytochrome P-450 (1.29 vs 2.15 nmol mg-1 protein) and the weights of liver and stomach increased significantly in PB treated rats, suggesting that the metabolizing enzymes for bumetanide are induced by pretreatment with PB. The 8-h urine output per 100 g body weight was not significantly different by pretreatment with PB although the amounts of bumetanide excreted in 8-h urine increased significantly in PB treated rats. It could be explained by the fact that the dose of bumetanide used results in urinary concentrations at the plateau of the concentration-effect relationship. Therefore, the alteration in the urinary excretion rate of bumetanide by pretreatment with PB would not alter the diuretic effect. In 3-MC treated rats, pharmacokinetic and pharmacodynamic parameters were not significantly different and it suggested that the metabolizing enzymes for bumetanide are not induced by pretreatment with 3-MC although the contents of hepatic cytochrome P-450 and the weights of liver and stomach increased significantly by pretreatment with 3-MC.

The pharmacokinetics and pharmacodynamics of bumetanide in normal subjects.

The pharmacokinetics and pharmacodynamics of bumetanide (1 mg) administered either orally or intravenously were studied in a group of normal subjects using high-pressure liquid chromatography. A two-compartment model adequately fitted the intravenous data. Renal clearance (85 ml min-1) contributed 65% to the total elimination of bumetanide irrespective of whether a model-dependent or model-independent method was used. Oral administration of bumetanide elicited a greater and a more prolonged pharmacological response than did intravenous bumetanide. An attempt is made to relate the pharmacokinetics of the drug to its pharmacodynamics.

Thermal dehydration of the rat: distribution of losses among tissues.

ARTICLESThermal dehydration of the rat: distribution of losses among tissuesWM Wallace, K Goldstein, A Taylor, and TM TereeWM Wallace, K Goldstein, A Taylor, and TM TereePublished Online:01 Dec 1970https://doi.org/10.1152/ajplegacy.1970.219.6.1544MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByCorticospinal and peripheral responses to heat-induced hypo-hydration: potential physiological mechanisms and implications for neuromuscular function1 April 2022 | European Journal of Applied Physiology, Vol. 122, No. 8Effect of short-term water restriction on oxidative and inflammatory status of sheep ( Ovis aries ) reared in Southern ItalySmall Ruminant Research, Vol. 162Nanoparticle Inhalation Impairs Endothelium-Dependent Vasodilation in Subepicardial ArteriolesJournal of Toxicology and Environmental Health, Part A, Vol. 72, No. 24Effects of water deprivation on drug pharmacokinetics: Correlation between drug metabolism and hepatic CYP isozymes12 September 2008 | Archives of Pharmacal Research, Vol. 31, No. 8Effects of water deprivation on the pharmacokinetics of metformin in rats1 January 2007 | Biopharmaceutics & Drug Disposition, Vol. 28, No. 7Expression of cytochrome p-450s and glutathiones-transferases in the rat liver during water deprivation: effects of glucose supplementation1 January 2001 | Journal of Applied Toxicology, Vol. 21, No. 2Body Fluid Balance During Heat Stress in Humans1 January 2011The effect of water deprivation on the pharmacokinetics of methotrexate in ratsBiopharmaceutics & Drug Disposition, Vol. 16, No. 3Effects of water deprivation for 48 hours on the pharmacokinetics and pharmacodynamics of furosemide in ratsJournal of Clinical Pharmacy and Therapeutics, Vol. 20, No. 1Effects of water deprivation on the pharmacokinetics and pharmacodynamics of bumetanide in ratsBiopharmaceutics & Drug Disposition, Vol. 14, No. 6Glycerol-induced hyperhydration: Its effects on fluid compartments in the ratLife Sciences, Vol. 53, No. 23Fluid compartmentation in skeletal muscle and carcass of Mus cusculus acclimated to water scarcityComparative Biochemistry and Physiology Part A: Physiology, Vol. 87, No. 3Water content and distribution of tritiated water in tissues of Australian desert rodentsComparative Biochemistry and Physiology Part A: Physiology, Vol. 45, No. 3The effect of water deprivation and hypertonic salt injection on several rodent species compared with the albino ratComparative Biochemistry and Physiology Part A: Physiology, Vol. 44, No. 2 More from this issue > Volume 219Issue 6December 1970Pages 1544-1548 Copyright & PermissionsCopyright © 1970 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1970.219.6.1544PubMed5485671History Published online 1 December 1970 Published in print 1 December 1970 Metrics