Pharmakokinetik von Digitoxin bei chronischer Niereninsuffizienz^*

Abstract

Digitoxin concentration, measured by radio-immunoassay, was significantly lower in 51 patients in chronic renal failure (23.2 +/- 7.8 mug/l) than in 29 patients in heart failure (26.5 +/- 7.3 mug/l), although both groups were on the same maintenance dose of 0.1 mg daily. Despite a normal serum albumin concentration, digitoxin protein binding was less in uraemic patients than in those with normal renal function. Renal failure did not affect intestinal digitoxin absorption. In patients in chronic renal failure elimination half-time was significantly shorter (5.7 +/- 0.9 days) than in healthy controls (7.6 +/- 1.6 days). There was no significant difference in the excretion of water-soluble ("cardioinactive") digitoxin metabolites in urine between patients in chronic renal and those in heart failure. In patients with normal renal function, of dichloromethane-soluble (cardioactive) metabolites only digitoxin could be demonstrated by thin-layer chromatography. The results indicate that patients in chronic renal failure can safely be given the same dose as those with normal renal function, without danger of over- or underdosage.

Protein Binding of Cardiac Glycosides in Disease States

“…I g / IOOmO compared with patients with heart insufficiency and mean serum albumin uf 3.2g/ i OOm!. The uraemic patients studied by Peters et al (1977) had more advanced renal failure than our patients, which might explain the discrepancies in the results. On the other hand, neither study found any change in the serum protein binding of digitoxin in patients on haemodialysis when the samples were taken before the start of hemodialysis.…”

“…No change in digitoxin protein binding was found in non-dialysis patients with a mean serum creatinine of 6. 7mg/ I OOml and a mean serum creatinine clearance of 19.9ml/min (Storstein, 1976a; In contrast, Peters et al (1977) found a decrease in digitoxin protein binding in non-dialysis patients with uraemia (mean serum creatmme 12.4mg/l OOml, mean serum albumin 3. I g / IOOmO compared with patients with heart insufficiency and mean serum albumin uf 3.2g/ i OOm!.…”

Digitalis in Chronic Renal Insufficiency

“…When renal function is im paired, the renal clearance of digitoxin de creases, while the extrarenal clearance in creases [61], resulting in unchanged total clearance. Increased extrarenal clearance of digitoxin in renal failure is apparently not the result of increased hepatobiliary clearance, but due to increased intestinal secretion [62], In contrast to previous reports [63], 12-betahydroxylation of digitoxin to digoxin does not occur to a major extent in uremic patients [51]. There is still some controversy as to the actual scrum concentrations of the relatively bioinactive metabolite dihydrodigitoxin in uremic patients [64], Because of unchanged total body clearance, steady-state plasma concentrations of digitoxin are not increased when patients with renal insufficiency are given normal loading and maintenance doses.…”

“…(table II) Bioavailability As a result of galenic differences, median bioavailability of various digoxin prepara tions varies between 60 and 70% and that of bcta-acetyldigoxin or methyldigoxin between 80 and 90% [47], In contrast, the bioavail ability of digitoxin is quite constant and is almost 100% [48,49]. Renal insufficiency does not alter the bioavailability of digitalis preparations [50,51]. However, the concom itant administration of intestinal phosphate binders (aluminum hydroxide) has been re ported to diminish by 25% gastrointestinal absorption and bioavailability of digoxin.…”

Disease-related Alterations in Cardiac Glycoside Disposition

“…This compares with 12.7% of the dose in 6 normal subjects. Although urine collections were incomplete and may therefore have underestimated the actual urinary elimination of digitoxin, these findings have been confirmed in other studies (Peters et al, 1977;Storstein, 1974a,b). Storstein found that an average of 13.6 % of the daily digitoxin dose was excreted in the urine at steady-state by 12 patients with reduced renal function (creatinine clearance: 6.6mIl min) compared with 35.7 % of the daily dose in II patients with mild renal impairment (creatinine clearance: 64ml/ min).…”