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.
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.
Since 1929 diguanides have been known to produce a hypoglycaemic effect in animals, but it was not until 1957 that phenylethyldiguanide (phenformin) and dimethyldiguanide (metformin) were tried in man. Related compounds, the guanidine derivatives, were shown to have a hypoglycaemic effect in animals (Watanabe, 1918). Frank et al. (1926) gave a full description of the effect of decamethylene-diguanidine (" synthalin ") on diabetic patients, and the clinical scope appears to be similar to that of phenformin and metformin. Toxic effects, mainly on the gastrointestinal tract but occasionally involving the liver and kidneys (Frank, 1928), discouraged its further use.
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