Pharmacokinetics of digoxin and its 4'''-acetyl- and methylderivates in the rat.

Abstract

The kinetics of absorption, of changes in blood concentration, and of biliary excretion after the i.v. and i.d. administration of 40 μCi each, of digoxin, 4‴-acetyldigoxin and 4‴-methyldigoxin were studied in biliary fistula rats. The highest blood concentrations were found after the i.v. administration of 4‴-methyldigoxin, which decline with a half life time of 10 h, compared with 5.6 and 4.5 h for 4‴-acetyldigoxin and digoxin respectively. 71%, 55% and 17% of the dose were excreted in the bile within 12 h after the i.v. administration of digoxin, 4‴-acetyldigoxin and 4‴-methyldigoxin. The blood concentrations observed after the i.d. administration of digoxin and 4‴-acetyldigoxin show almost identical pharmacokinetics with respect to height and elimination velocity (half life 7.0 h for digoxin and 7.5 h for 4‴-acetyldigoxin). In contrast, following the i.d.administration of 4‴-methyldigoxin, blood concentrations, which were twice as high, were observed and declined with the same half life as after the i.v. administration. Determination of the disappearance rates of these glycosides from the intestinal lumen reveals a biphasic course of absorption. A first phase, with k values of 0.4, 0.5, 1.2 for digoxin, 4‴-acetyldigoxin and 4‴-methyldigoxin respectively is followed by a second phase with k values of 0.04, 0.04, 0.001 for digoxin, 4‴-acetyldigoxin and 4‴-methyldigoxin. Thus, 4‴-methyldigoxin is almost completely absorbed within the first two hours, while digoxin and 4‴-acetyldigoxin continue to be absorbed during the following hours. The absorption velocity of digoxin from the ileum was found to be one half of that seen in the duodenum. But this slow absorption, as well, follows a biphasic course. The data indicate that 4‴-methyldigoxin is absorbed at a distinctly higher rate than 4‴-acetyldigoxin and digoxin. Acetylation in 4‴ position evidently provides no important advantage with respect to absorption. While this study allows the determination of absorption and excretion velocities, no account of absorption quotes is given.