The pharmacokinetics and pharmacodynamics of the diuretic bumetanide in hepatic and renal disease.

Abstract

1Bumetanide (1 mg) was given orally and intravenously to a group of patients with chronic renal failure (n = 6) and to another group with cirrhosis of the liver (n = 8). 2 The pharmacokinetics, using a two-compartment model, and the pharmacodynamics of the drug in these patients were compared with those previously obtained for normal subjects. 3 In the renal group serum bumetanide concentrations were higher than for the normal subjects and the terminal half-lives were significantly prolonged (P < 0.001). A decreased whole body clearance was attributable to a low renal clearance of drug, the non-renal clearance being significantly increased (P < 0.01). 4 For the patients with liver disease, serum bumetanide concentrations were higher than for the renal group, and the terminal half-lives were significantly further prolonged (P < 0.001). Both non-renal and renal clearances were significantly reduced (P < 0.001). 5 Absorption rates were not significantly altered in either group and the values of F (bioavailability) were 0.82 and 0.95 for the patients with renal disease and hepatic disease, respectively. 6 A poor pharmacodynamic response and a reduced bumetanide excretion rate were observed for the patients with chronic renal failure, whereas with hepatic disease normal bumetanide excretion rates were observed with an impaired diuretic response.

Bioavailability of Bumetanide in Grossly Oedematous Patients

“…The volume of distribution of oedematous patients in our study (33.4L) is markedly greater than that of other studies (9.9L) [Marcantonio et al 1983], suggesting perhaps that bumetanide does penetrate easily into oedema fluid. Similarly, the areas under the curves show large differences which may be attributable to the large volume of distribution, which in turn is possibly a reflection of the extent of the hypoalbuminaemia.…”

“…The relative bioavailability of oral bumetanide in these oedematous patients was the same as that in patients with renal impairment (Marcantonio et al 1983), although there is no evidence that the patients in that study were oedematous to any sig- nificant extent. Furthermore, the bioavailability in normal patients (F = 0.89) is not significantly different (Marcantonio et al 1982).…”

Apical Voltage-Driven Urate Efflux Transporter NPT4 in Renal Proximal Tubule

“…Since the administration of standard doses for loop diuretics 4 and 5 and thiazide diuretic 2 in adults is about 1-2 mg, 40-80 mg, and 500-1000 mg, respectively, the estimated C max plasma concentration for these drugs will be 0.4-0.8 µM (bumetanide), 8-17 µM (furosemide), and 120-240 µM (chlorothiazide). These plasma concentrations for loop diuretics 4 and 5 are supported by pharmacokinetic data reported by Marcantonio et al (1983) [19] and Gottlieb et al (1998). [20] The plasma concentrations for these diuretic drugs have been related to their IC 50 values on basolateral OAT1 and OAT3 transporters (7.6 and 0.75 µM for 4, 18.0 and 7.31 µM for 5, and 3.78 and 65.3 µM for 2) reported earlier.…”

Diuretic Resistance: Mechanisms and Therapeutic Strategies

“…In the latter group, diuretic resistance is purely pharmaco kinetic in etiology, whereas in patients with cirrhosis a pharmacodynamic mechanism prevails. Renal clearance of loop diuretics in patients with cirrhosis is normal if they have preserved glomerular filtration rates [27][28][29][30][31][32][33]. For bumetanide and torasemide there may actually be increased delivery of diuretic into the urine compared with healthy subjects, be cause non-renal clearance of these diuretics is diminished concomitant with decreased he patic function [27], This compromised nonrenal clearance allows higher serum concen trations to prevail, which in the face of normal renal clearance causes greater total amounts of diuretic to be delivered to the urinary site of action.…”

“…Renal clearance of loop diuretics in patients with cirrhosis is normal if they have preserved glomerular filtration rates [27][28][29][30][31][32][33]. For bumetanide and torasemide there may actually be increased delivery of diuretic into the urine compared with healthy subjects, be cause non-renal clearance of these diuretics is diminished concomitant with decreased he patic function [27], This compromised nonrenal clearance allows higher serum concen trations to prevail, which in the face of normal renal clearance causes greater total amounts of diuretic to be delivered to the urinary site of action. The normal or even increased deliv ery of diuretic into the urine in patients with cirrhosis means that there is no rationale for administering increased doses of loop diuret ics to such patients; a ceiling dose in patients with cirrhosis is thereby the same as in healthy subjects.…”