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

1996; Wiley; Volume: 119; Issue: 5 Linguagem: Inglês

10.1111/j.1476-5381.1996.tb15775.x

1476-5381

Ulrich Mayer, Els Wagenaar, Jos H. Beijnen, Johan W. Smit, Dirk K. F. Meijer, Judith van Asperen, Piet Borst, Alfred H. Schinkel,

Epilepsy research and treatment

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.