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

A 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 flow 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 conducted 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.

Prognostic Value of Elevated Levels of Intestinal Microbe-Generated Metabolite Trimethylamine-N-Oxide in Patients With Heart Failure

“…Several of these features of altered intestinal function have been observed in patients with HF (3,4). Meanwhile, the impact of progressive venous congestion in subsets of patients with significant congestive signs and symptoms may lead to unwanted consequences of abdominal congestion, including adverse impact on drug absorption and pharmacokinetics (5,6), and renal glomerular and tubular dysfunction resulting from raised intra-abdominal pressures (7,8). …”

Drug Absorption in the Management of Congestive Heart Failure: Loop Diuretics

“…This promotes hepatosplanchnic congestion. 18 14 The net result of an increase in the apparent partition coefficient and decrease in splanchnic perfusion secondary to CHF is a decreased migration of intraluminal drug into the systemic circulation (manifested as a decrease in the fraction of the dose absorbed).…”

“…For example, the absorption rate for digoxin is influenced by changes in intestinal blood flow as may be experimentally induced by coadministration of the vasodilator epoprostenol. [17][18] The absorption rate of most drugs shows an intermediate dependence on blood flow rate; relatively large decreases from a normal mesenteric blood flow rate are required to produce a relevant change in absorption rate. In general, the rate of drug absorption will be unaffected by normal physiologic variability in mesenteric blood flow since mesenteric blood flow is seldom the rate-limiting step in the process of absorption.…”

“…Ordinarily, changes in mesenteric blood flow that result from disease or drug effects must be substantial and sustained for some period of time to significantly influence drug absorption. 18…”

Physiologically Based Pharmacokinetic Model for Terbinafine in Rats and Humans

“…where k a and k s are the absorption and reabsorption rate constants, respectively; C Lum and C SI are the concentrations of terbinafine in the intestinal lumen and small intestine, respectively; V Lum and V SI are the volumes of the intestinal lumen (V Lum ϭ 1 liter [7]) and small intestine, respectively; and Kp SI is the small intestine tissue-to-plasma partition coefficient. Consideration of enterohepatic recirculation.…”