Effect of basic drugs on the hepatic uptake of ouabain by sinusoidal plasma membrane vesicles isolated from rat liver.
Although antiarrhythmic drugs are used to treat digitalis-induced cardiac disorders, some of these drugs have been reported to increase the serum digoxin concentration in patients, causing the severe side-effects. We have previously shown that many basic drugs including antiarrhythmic drugs inhibited the hepatic uptake of cardiac glycosides into isolated rat hepatocytes, which could be a cause for the increased serum digoxin concentration. The present study was designed to examine the mechanism of this inhibition using isolated rat sinusoidal plasma membrane vesicles. The effect of nine basic drugs (dipyridamole, nifedipine, verapamil, chlorpromazine, lidocaine, quinidine, ajmaline, disopyramide, and propranolol) on the uptake of ouabain was studied. Quinidine reduced the initial uptake rate of ouabain (30 s) while it did not change the uptake of ouabain in an equilibrium condition (30 min). Other basic drugs, such as verapamil, dipyridamole, and nifedipine also significantly reduced the initial uptake rate of ouabain. These basic drugs had no effect on the membrane fluidity. The inhibitory effects on the vesicular uptake were significantly correlated with the inhibitory effects on ouabain uptake by the isolated rat hepatocytes. These findings may suggest that the mechanism of the inhibition involves the inhibition of the transport process via the sinusoidal plasma membrane.
Okudaira
K
K
Division of Xenobiotic Metabolism and Disposition, National Institute of Hygienic Sciences, Tokyo, Japan.
Yachi
K
K
Sawada
Y
Y
Sugiyama
Y
Y
Iga
T
T
Hanano
M
M
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology*; D002463:Cell Membrane Permeability; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D010042:Ouabain / Q000493:pharmacokinetics*; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014316:Tritium
D014316:Tritium; D010042:Ouabain; D011802:Quinidine