Search

One hr, 3 hr and 6 hr after i.v. injection of tritiated gitoxin, digoxin and digitoxin to the guinea-pig, the chloroform-insoluble metabolites, mainly conjugates known to be cardio-inactive, represent two thirds of the cardiac glycoside and metabolites content of plasma for gitoxin, half for digitoxin and one quarter for digoxin. Most of the compounds taken up by the myocardium are chloroform-soluble and may be considered as cardio-active. Considering the nature and proportions of the unchanged cardiac glycoside and its cardio-active metabolites in the myocardium of the guinea-pig, the cardiac effects that would be measured after administration of digoxin ar due to unchanged digoxin only; after administration of digitoxin, these effects are partly due to unchanged digitoxin but also to 12 beta-hydroxylated metabolites; after administration of gitoxin, besides unchanged gitoxin, the hydrolysis products of the sugar chain of gitoxin may contribute to the cardiac effects. The data obtained in plasma and in myocardium between 1 and 6 hr after administration of digoxin or gitoxin show that the distribution of the unchanged cardiac glycoside and each chloroform-soluble metabolite, from plasma to myocardium, is achieved 1 hr after administration. This situation does not occur with digitoxin and its metabolites.

The aim of the present investigation was to reevaluate the pharmacokinetic and pharmacodynamic parameters of gitoxin in man. Gitoxin given as a solution is quasi-completely absorbed after oral administration in a fasting man. A dose of 1.5 mg modifies the left ventricular ejection time index (LVETI) as digoxin or digitoxin does. The biological half-life of gitoxin calculated on the basis of plasma concentrations or urinary data is about one day. The urinary elimination of gitoxin is smaller than 21% of the dose. Therefore the two main advantages of gitoxin versus digoxin or digitoxin are: 1) its short biological half-life and 2) its elimination being less dependent on the renal function of the patient.

Kinetics and metabolism of 3H-gitoxin were determined in the guinea-pig after the i.v. administration of 80 microgram gitoxin/kg. The time course of plasma concentration and urinary amounts remaining to be excreted were described according to the three-compartment linear body model. Apparent half-lives of 4.98 +/- 0.16 hr (plasma) and 24.0 +/- 0.5 hr (urine) were found according to the CH2Cl2-soluble radioactivity. The apparent volume of central compartment and the apparent volume of distribution were estimated with 0.44 +/- 0.05 l/kg and 14.33 +/- 1.131/kg respectively. During 96 hr, approximatively 5.3% of the radioactivity given were eliminated via the kidneys whereas almost 78.7% were recovered in faeces. In animals with bile-duct cannulated, approximatively 82.6% of the dose given were excreted in bile during 6 hr. The hepatic degradation of gitoxin was so fast that almost 70% of the radioactivity recovered in plasma, urine and bile samples after 2 hr could no longer be extracted by dichloromethane. In the lipophilic extracts diginatin and its derivatives were found as possible metabolites of gitoxin. At least four polar metabolites hardly hydrolysable by beta-glucuronidase and by arylsulfatase were detected by TLC in the aqueous extracts from the gastro-intestinal excretions.