Physiologic Pharmacokinetic Modeling of Gastrointestinal Blood Flow as a Rate-Limiting Step in the Oral Absorption of Digoxin: Implications for Patients with Congestive Heart Failure Receiving Epoprostenol

Abstract

AbstractA previously validated physiologically based pharmacokinetic model was used to examine whether epoprostenol-induced increases in gastrointestinal blood flow (Qg) could alter digoxin systemic bioavailability to a clinically significant extent in severe congestive heart failure (CHF) patients. A series of simulations was conducted in which the influences of apparent gut tissue-to-plasma partition coefficient (Kg) and Qg on digoxin bioavailability were evaluated. Since epoprostenol also increases blood flow to the liver and kidneys, the effect of concurrent increases in regional blood flow to these organs on digoxin bioavailability also was evaluated. A range of Qg was studied from 25 L/h (assumed mesenteric arterial low in CHF) to 65 L/h (portal venous flow in normal adults), and the area under the simulated digoxin concentration–time curve was used to calculate absolute digoxin bioavailability in each case. Simulations were onducted at a range of Kg from 1 to 50 (physiologically relevant range 5–25). At low values of Kg, the influence of changes in Qg on digoxin bioavailability was minimal. However, as apparent distribution into gut tissue increased (consistent with visceral congestion), the effect of changes in Qg was more substantial. In the physiologically relevant range of Kg, 40–160% increases in Qg were associated with approximately 6–40% increases in digoxin bioavailability. Therefore, the decrease in digoxin oral clearance previously observed in CHF patients receiving epoprostenol may be ascribed to increases in digoxin bioavailability, secondary to epoprostenol-induced increases in Qg.