Pharmacokinetics of beta-methyldigoxin in healthy humans III: Pharmacodynamic correlations

Significant decreases in left ventricular ejection time and heart rate were observed after the oral and intravenous administration of beta-methyldigoxin. The time course of this action correlated with the time course of beta-methyldigoxin and its active metabolite, digoxin, in their deepest pharmacokinetic compartments and not with their plasma levels. This pharmacodynamic activity peaked (decrease of 6.3% at 0.6 mg iv and 3.5% at 0.3 mg iv; decrease of 3.8% at 0.6 mg po and 4.5% at 0.3 mg po) at about 10 hr, concomitantly with the amounts of beta-methyldigoxin in its deepest compartment and showed a terminal half-life equivalent to the 41 hr for beta-methyldigoxin. The relative peak heights and area under the ejection time-time curves indicated a linear dose-response relationship on intravenous administration and an effect greater than that reported for larger amounts of digoxin. The time course of heart rate action correlated (8.3 and 12.5% decreases with 0.3 and 0.6 mg iv, respectively; 6.5 and 9.5% decreases with 0.3 and 0.6 mg po, respectively) with the time course of beta-methyldigoxin and its metabolite digoxin in shallower pharmacokinetic compartments (peaks at approximately 80 min intravenously and 135 min orally), and significant effects had disappeared by 10 hr after drug administration. This finding indicated that the biophases differ for ejection time and heart rate action. Mean arterial blood pressure could not be correlated with the time course of drug, although a small consistent decrease (4-8%) was observed from 22 to 72 hr after drug administration.