The binding of gitoxin, digitoxin and digoxin to human plasma proteins was measured by ultracentrifugation and equilibrium dialysis. At concentrations in the range of therapeutic plasma levels, protein binding amounted, respectively, to 85, 92 and 20%, the last two values being consistent with data reported in the literature. The affinity of purified human albumin was not significantly different for the three cardiac glycosides tested. No other protein than albumin was found to bind gitoxin in human plasma.
The effect of torasemide, a new orally and parenterally active diuretic agent, on the renal mechanisms of dilution and concentration was studied in 6 healthy volunteers. The experimental conditions included water and osmotic diuresis. Torasemide caused maximal chloruresis and natriuresis during the 20-40 min after administration. The effect was more pronounced under osmotic diuresis and persisted throughout the 100 min of those experiments. A distinct effect both on free water clearance (CLH2O) during water diuresis and tubular reabsorption of solute free water (TcH2O) during osmotic diuresis strongly suggests that the major site of action of torasemide is the ascending limb of the loop of Henle. Comparison with furosemide under osmotic diuresis indicates longer abolition of TcH2O/GFR by torasemide in keeping with the fact that its half-life is 2- to 3-times longer than that of furosemide.
Hepatic clearance of gitoxin has been studied in the rabbit and compared with that of digoxin using an isolated perfused liver technique. During 1.5 hour perfusions with a modified Krebs-Henseleit solution, gitoxin perfusate levels decreased biexponentially; the distribution and elimination half-lives were estimated to be 0.14 and 1.25 hour, Vd area to be 95.5 ml.g-1 and intrinsic metabolic clearance to be 1.98 ml.min-1.g-1. During 1.5 hour perfusions with modified Krebs-Henseleit solution containing 2.7% bovine serum albumin, gitoxin perfusate levels decreased monoexponentially. This is probably due to protein binding which moderates hepatic uptake so that distribution is not yet complete after 1.5 hour and it is therefore impossible to discriminate the two phases. This was confirmed by 5 hour perfusion experiments with an emulsion of perfluorocarbon in the modified Krebs-Henseleit solution also containing 2.7% bovine serum albumin, during which gitoxin levels decreased biexponentially. Distribution and elimination half-lives have been estimated to be 0.31 and 5.54 hours, Vd area to be 139 ml.g-1 and intrinsic metabolic clearance to be 1.36 ml.min-1.g-1. Gitoxin has been compared in these experimental conditions with digoxin, one of the most often used cardiotonic's. Distribution and elimination half-lives of digoxin were estimated to be 0.34 and 4.52 hours, Vd area to be 46.5 ml.g-1 and intrinsic metabolic clearance to be 0.17 ml.min-1.g-1. Other pharmacokinetic parameters (alpha, beta, V1, V2...) also have been calculated for these three types of perfusion experiments.
Hepatic clearance of 3H-gitoxin was studied in the rabbit using an isolated perfused liver technique with an emulsion of a perfluorocarbon. The liposoluble material in the perfusion medium was extracted with dichloromethane, and gitoxin was assayed in the extract by high performance liquid chromatography. Pharmacokinetic parameters were estimated for the liposoluble (dichloromethane soluble) material in the water phase obtained by centrifugation of the emulsion, for the liposoluble material and unchanged gitoxin in the total emulsion. Distribution and elimination half-lives of the liposoluble fraction in the water phase, were estimated to be 0.47 and 4.80 hours respectively, Vd to be 148 ml.g-1 and intrinsic clearance to be 1.16 ml.min-1.g-1; these parameters were compared with those of a previous study with unlabelled gitoxin. Distribution and elimination half-lives of the liposoluble compounds in the emulsion were estimated to be 0.48 and 4.62 hours, Vd to be 47 ml.g-1 and intrinsic clearance to be 1.07 ml.min-1.g-1; these data were compared with those of the liposoluble compounds in the water phase. Distribution and elimination half-lives of unchanged gitoxin in the emulsion were estimated to be 0.22 and 0.70 hour, Vd to be 59 ml.g-1 and intrinsic clearance to be 11.4 ml.min-1.g-1; these data were compared with those of the liposoluble compounds in the emulsion. The subcellular distribution of gitoxin and its metabolites in the liver indicated that 79% of the radioactivity was found in the soluble fraction, no significant binding occurring in the mitochondrial and microsomal fractions.
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