Assessment of methodology in single-dose studies of digoxin bioavailability

Eight healthy males received 0.75 mg of digoxin by ten modes of administration in a single-dose multicrossover bioavilability study. Digoxin concentration in multiple blood samples drawn after each dose and in six consecutive 24-hour urine collections were used to calculate the areas under the 4-, 8-, and 24-hour serum concentration curve (A-4, A-8, A-24), and the excretion of digoxin during 1 day (U-1) and 6 days (U-6) following each dose. All five methods of assessment gave very similar information on bioavailability. Individual values of A-4 and A-8 were highly correlated (r=0.973) and had similar variability. A-24 was more variable than A-4 and A-8, and was not as well correlated with either. U1- and U-6 were highly correlated (r=0.944), and had nearly identical variability which was less than that of any of the area measures. Thus, urinary excreation data provides more reliable and reproducible information about completeness of absorption of digoxin than data based upon serum concentrations. Extending the period of urine collection beyond 1 day or the blood sampling period beyond 4 or 8 h does not enhance the reliability or usefulness of digoxin bioavailability studies.