PHYSIOLOGICAL PHARMACOKINETIC MODELING OF GASTROINTESTINAL BLOOD-FLOWAS A RATE-LIMITING STEP IN THE ORAL ABSORPTION OF DIGOXIN - IMPLICATIONS FOR PATIENTS WITH CONGESTIVE-HEART-FAILURE RECEIVING EPOPROSTENOL

A previously validated physiologically based pharmacokinetic model was used to examine whether epoprostenol-induced increases in gastrointes tinal blood flow (Q(g)) could alter digoxin systemic bioavailability t o a clinically significant extent in severe congestive heart failure ( CHF) patients. A series of simulations was conducted in which the infl uences of apparent gut tissue-to-plasma partition coefficient (K-g) an d Q(g) on digoxin bioavailability were evaluated. Since epoprostenol a lso increases blood flow to the liver and kidneys, the effect of concu rrent increases in regional blood flow to these organs on digoxin bioa vailability also was evaluated. A range of Q(g) was studied from 25 L/ h (assumed mesenteric arterial flow in CHF) to 65 L/h (portal venous f low in normal adults), and the area under the simulated digoxin concen tration-time curve was used to calculate absolute digoxin bioavailabil ity in each case. Simulations were conducted at a range of K-g from 1 to 50 (physiologically relevant range 5-25). At low values of K-g, the influence of changes in Q(g) on digoxin bioavailability was minimal. However, as apparent distribution into gut tissue increased (consisten t with visceral congestion), the effect of changes in Q(g) was more su bstantial. In the physiologically relevant range of K-g, 40-160% incre ases in Q(g) were associated with approximately 6-40% increases in dig oxin bioavailability. Therefore, the decrease in digoxin oral clearanc e previously observed in CHF patients receiving epoprostenol may be as cribed to increases in digoxin bioavailability, secondary to epoproste nol-induced increases in Q(g).