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

被引:250
作者
Mayer, U
Wagenaar, E
Beijnen, JH
Smit, JW
Meijer, DKF
vanAsperen, J
Borst, P
Schinkel, AH
机构
[1] NETHERLANDS CANC INST, DIV MOL BIOL, NL-1066 CX AMSTERDAM, NETHERLANDS
[2] NETHERLANDS CANC INST, DEPT CLIN CHEM, NL-1066 CX AMSTERDAM, NETHERLANDS
[3] EUROPEAN CANC CTR, AMSTERDAM, NETHERLANDS
[4] SLOTERVAART HOSP, DEPT PHARM, AMSTERDAM, NETHERLANDS
[5] UNIV GRONINGEN, DEPT PHARMACOKINET & DRUG DELIVERY, GRONINGEN, NETHERLANDS
关键词
multidrug resistance; drug disposition; blood-brain barrier; knockout mice; enterohepatic circulation; intestinal mucosa; P-glycoprotein;
D O I
10.1111/j.1476-5381.1996.tb15775.x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:1038 / 1044
页数:7
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