Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdr1a P-glycoprotein

1 We have used mice with a disrupted mdrla P-glycoprotein gene (mdrIa (-/-) mice) to study the role of P-glycoprotein in the pharmacokinetics of digoxin, a model P-glycoprotein substrate. 2 [K-3]-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 [H-3]-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 [H-3]-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 [H-3]-digoxin was not dramatically decreased (24% in wildtype mice versus 16% in mdrIa (-/-) mice). 5 After a single bolus injection, brain levels of [H-3]-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 similar to 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 [H-3]-digoxin from the systemic circulation and to the pattern of [H-3]-digoxin disposition, and they underline the importance of P-glycoprotein for the blood-brain barrier.