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

作者：Ulrich Mayer, Els Wagenaar, Jos H. Beijnen, Johan Willem Smit, Dirk K. F. Meijer, Judith van Asperen, Piet Borst, Alfred H. Schinkel · 发表于：British Journal of Pharmacology · 年份：1996 · DOI：10.1111/j.1476-5381.1996.tb15775.x · 被引用次数：284 · 研究领域：Drug Transport and Resistance Mechanisms、Pharmacological Effects and Toxicity Studies、Epilepsy research and treatment

1. We have used mice with a disrupted mdr 1a P-glycoprotein gene (mdr 1a (-/-) 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 mdr 1a 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 mdr 1a (-/-) 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 mdr 1a (-/-) mice. Biliary excretion of [3H]-digoxin was not dramatically decreased (24% in wild-type mice versus 16% in mdr 1a (-/-) mice). 5. After a single bolus injection, brain levels of [3H]-digoxin in wild-type mice remained very low, whereas in mdr 1a (-/-) mice these levels continuously increased over a period of 3 days, resulting in a approximately 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 ...