Decreased digoxin cardioinactive-reduced metabolites after administration as an encapsulated liquid concentrate.

The generation by intestinal bacteria of large amounts of cardioinactive metabolites of digoxin with a reduced lactone ring (digoxin reduction products, or DRP) may be associated with increased dosage requirements. Since DRP excretion varies inversely with bioavailability, we compared the 6-day urinary excretion (CUE) of digoxin and DRP after 0.4-mg doses of an encapsulated liquid concentrate and a standard tablet in 22 normal subjects known to form substantial amounts of DRP. Mean (+/- SE) CUE of digoxin was greater with the capsules than the tablets (195.9 +/- 8.6 and 137.5 +/- 6.3 micrograms). CUE of DRP was less after the capsules (60.8 +/- 5.5 and 102.7 +/- 9.5 micrograms). Percent DRP was greater after the tablets in every subject (mean for tablets, 41.2 +/- 2.7%; capsules, 23.5 +/- 1.8%). Patterns of DRP excretion differed with the two preparations, probably reflecting differences in the routes whereby digoxin reached the colon. The use of highly bioavailable capsules in subjects with heavy DRP production should minimize metabolic inactivation during digoxin therapy.

The development and application of a radioimmunoassay for dihydrodigoxin, a digoxin metabolite.

The cardioinactive digoxin metabolite, dihydrodigoxin, has been conjugated to bovine serum albumin and to bovine pancreatic ribonuclease by the periodate oxidation method. Rabbits immunized with the dihydrodigoxin-bovine serum albumin conjugate formed antibodies which bound a radioiodinated dihydrodigoxin-ribonuclease conjugate. This binding was inhibited by dihydrodigoxin. After affinity chromatography on a digoxin-ribonuclease-Sephacryl immunoadsorbent to remove antibodies which cross-reacted with digoxin, dihydrodigoxin was 300 times more effective than digoxin in inhibiting the binding of tracer by antibody. Digoxin-absorbed antidihydrodigoxin antibodies were coupled to Sephacryl and were used to develop a solid-phase radioimmunoassay capable of detecting 250 to 500 pg of dihydrodigoxin in 1 ml of human serum or urine. This radioimmunoassay has been used to define the pharmacokinetics of the metabolite in four normal human volunteers who ingested 125 to 500 micrograms of dihydrodigoxin by mouth. Dihydrodigoxin was quickly absorbed, with maximal serum concentrations achieved within 45 to 105 min, followed by a rapid fall in serum immunoreactivity over 2 to 4 hr and then by a slower, more gradual decline. The terminal half-life (beta) in serum varied from 4.24 to 11.9 hr (mean +/- S.E. = 8.1 +/- 1.3 hr). Most of the administered dose was excreted in the urine, with cumulative urinary recovery varying inversely with the dose. Urinary half-lives averaged 13.8 +/- 2.1 hr, and renal clearance rates were similar to those of creatinine. Dihydrodigoxin is rapidly absorbed and excreted in man and appears to be eliminated from the body at a faster rate than digoxin.

Inactivation of digoxin by the gut flora: reversal by antibiotic therapy.

In approximately 10 per cent of patients given digoxin, substantial conversion of the drug to cardioinactive, reduced metabolites (digoxin reduction products, or DRPs) occurs. The site and clinical importance of this conversion is unknown. In four normal volunteers taking digoxin daily for four weeks, urinary excretion of DRPs was greatest after a poorly absorbed tablet was ingested, and least after intravenous administration, Stool cultures from subjects known to make DRPs in vivo ("excretors") converted digoxin to DRPs; cultures from nonexcretors did not. Three excretors were given tablets for 22 to 29 days. A five-day course of erythromycin or tetracycline, administered after a base-line period of 10 to 17 days, markedly reduced or eliminated DRP excretion in urine and stool. Serum digoxin concentrations rose as much as twofold after antibiotics were given. We conclude that in some persons digoxin is inactivated by gastrointestinal bacteria. Changes in the enteric flora may markedly alter the state of digitalization.

Urinary excretion of reduced metabolites of digoxin.

The urinary excretion of the relatively cardioinactive reduced metabolites of digoxin, dihydrodigoxin and related compounds was measured by radioimmunoassay in 131 normal subjects during studies of the bioavailability of digoxin preparations. Digoxin reduction products (DRP) constitute more than 5 percent of the excretion of digoxin and its metabolites in one-third of the volunteers after the administration of single or multiple doses of digoxin. There was little or no output of DRP during the first 8 hours after a single dose, with maximal excretion usually occurring on the second day. Most subjects who excreted more than 5 percent DRP on one occasion did so with each subsequent exposure to digoxin. Six volunteers, however, in whom substantial amounts of DRP had previously been found, failed to excrete detectable quantities after subsequent doses. In two, this change occurred shortly after they took erythromycin. Urinary DRP were less after the intravenous administration compared to the oral administration of digoxin. After oral doses, DRP excretion tended to vary inversely with the bioavailability of the preparation. The findings are consistent with the hypothesis that DRP are formed as the result of the activity of a variable component of the intestinal flora. Prospective studies will be necessary to prove this hypothesis.