Substantial excretion of digoxin via the intestinal mucosa and prevention of long‐term digoxin accumulation in the brain by the mdrla P‐glycoprotein

Abstract

1 We have used mice with a disrupted mdrla P‐glycoprotein gene (mdrla (—/—)mice) to study the role of P‐glycoprotein in the pharmacokinetics of digoxin, a model P‐glycoprotein substrate. 2 [³H]‐digoxin at a dose of 0.2 mg kg⁻¹ was administered as a single i.v. or oral bolus injection. We focussed on intestinal mucosa and brain endothelial cells, two major pharmacological barriers, as the mdrla P‐glycoprotein is the only P‐glycoprotein normally present in these tissues. 3 Predominant faecal excretion of [³H]‐digoxin in wild‐type mice shifted towards predominantly urinary excretion in mdrla (—/—) mice. 4 After interruption of the biliary excretion into the intestine, we found a substantial excretion of [³H]‐digoxin via the gut mucosa in wild‐type mice (16% of administered dose over 90 min). This was only 2% in mdrla (—/—) mice. Biliary excretion of [³H]‐digoxin was not dramatically decreased (24% in wild‐type mice versus 16% in mdrla (—/—) mice). 5 After a single bolus injection, brain levels of [³H]‐digoxin in wild‐type mice remained very low, whereas in mdrla (—/—) mice these levels continuously increased over a period of 3 days, resulting in a ∼200 fold higher concentration than in wild‐type mice. 6 These data demonstrate the in vivo contribution of intestinal P‐glycoprotein to direct elimination of [³H]‐digoxin from the systemic circulation and to the pattern of [³H]‐digoxin disposition, and they underline the importance of P‐glycoprotein for the blood‐brain barrier.