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 pharmacokinetic s of digoxin, a model P-glycoprotein substrate. 2 [K-3]-digoxin at a d ose of 0.2 mg kg(-1) was administered as a single i.v. or oral bolus i njection. We focussed on intestinal mucosa and brain endothelial cells , two major pharmacological barriers, as the mdrla P-glycoprotein is t he only P-glycoprotein normally present in these tissues. 3 Predominan t faecal excretion of [H-3]-digoxin in wild-type mice shifted towards predominantly urinary excretion in mdrla (-/-) mice. 4 After interrupt ion of the biliary excretion into the intestine, we found a substantia l 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 (-/-) mi ce. Biliary excretion of [H-3]-digoxin was not dramatically decreased (24% in wildtype mice versus 16% in mdrIa (-/-) mice). 5 After a singl e bolus injection, brain levels of [H-3]-digoxin in wild-type mice rem ained 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 elimin ation of [H-3]-digoxin from the systemic circulation and to the patter n of [H-3]-digoxin disposition, and they underline the importance of P -glycoprotein for the blood-brain barrier.