Bumetanide binding to normal albumins and to albumin in renal failure.

Binding of bumetanide, a loop diuretic, to partially purified albumins from renal failure patients (RF-HA), and healthy subjects (N-HA), human serum albumin (HSA) and defatted-HSA (D-HSA), was studied with equilibrium dialysis at a constant albumin concentration and various ligand concentrations. Binding parameters (n and K) were estimated from Scatchard plots and with a non-linear two-binding site model computer program, assuming two classes of independent sites. The binding capacities (n1K1) decreased in the order N-HA > RF-HA > D-HSA > HSA. Computer estimates of K1 for the partially purified albumin preparations were not markedly different. However, the graphical estimate of K1 for N-HA was greater than that for RF-HA. When the degree of binding (r) was plotted as a function of the logarithm of the free bumetanide concentration, an asymptotic plateau was not observed, indicating that the protein binding sites were not saturated. Consequently, the calculated binding estimates may not adequately describe the binding of bumetanide.

Metabolism of the diuretic bumetanide in healthy subjects and patients with renal impairment.

The pharmacokinetics and metabolism of orally administered bumetanide were studied in five healthy subjects and in five patients with renal insufficiency. Healthy subjects excreted 51% of the dose as unchanged drug in the urine, whilst the patients with renal insufficiency excreted only 11% of the dose as bumetanide. Similarly the urinary excretion of the gamma-hydroxybutyl metabolite was reduced from 6% in healthy subjects to 2.3% in patients with renal impairment. In both groups of subjects the mean elimination half-life of the metabolite was greater than for bumetanide. The results indicate a possible accumulation of bumetanide and metabolite in patient with renal failure.

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

1 Bumetanide (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 less than 0.001). A decreased whole body clearance was attributable to a low renal clearance of drug, the non-renal clearance being significantly increased (P less than 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 less than 0.001). Both non-renal and renal clearances were significantly reduced (P less than 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.

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.

Precocious pseudopuberty due to a rare form of congenital adrenal hyperplasia. Biochemical investigation and pitfalls in interpretation of hormone assays.

The biochemical investigation is described of a boy who presented with precocious puberty at the age of 3 years 9 months due to a rare form of congenital adrenal hyperplasia (CAH), steroid 11 beta-hydroxylase deficiency. Serum androgen levels were grossly elevated (17 hydroxyandrogens 10 nmol/l, androstenedione 129 nmol/l), 17 hydroxyprogesterone was modestly elevated (21 nmol/l), while serum gonadotrophins were low and testes were prepubertal in size. The major differential diagnosis was between an androgen-producing tumour and CAH. Initial serum and urine corticosteroid concentrations and their responses to dexamethasone were diagnostically misleading, later found to be due to lack of specificity of the radioimmunoassays and fluorimetric methods employed. Elevated basal plasma ACTH levels and suppression of androgen and ACTH levels by dexamethasone strongly suggested CAH. Definitive diagnosis of an 11 beta-hydroxylase defect was established by capillary column gas liquid chromatography of urine which demonstrated excess androgen and 11-deoxycortisol metabolites but no cortisol metabolites. The diagnosis was confirmed by specific serum assays of 11-deoxycortisol, deoxycorticosterone, and cortisol. The contribution of hormone assays and a protocol for their use in the diagnosis and monitoring of precocious puberty is discussed.

Clinical trial of mefruside, a new diuretic.

A controlled clinical trial of a new diuretic-mefruside-is reported, in which it was compared with frusemide in 15 normal subjects and 15 patients with fluid retention. It was found to be an effective diuretic which, in the patients, produced a significantly greater excretion of water and electrolytes than an equal dose of frusemide. Its smooth prolonged action, maximal in the first 12 hours, made it of particular value for maintenance therapy. In a short-term trial on a further 15 hypertensive patients mefruside was shown to have a useful hypotensive action. The drug was well tolerated with minimal side effects.