Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdr 1a P-glycoprotein.
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 blood-brain barrier.
Mayer
U
U
Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Wagenaar
E
E
Beijnen
J H
JH
Smit
J W
JW
Meijer
D K
DK
van Asperen
J
J
Borst
P
P
Schinkel
A H
AH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004077:Digoxin / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004077:Digoxin