The stereoisomers quinine and quinidine exhibit a marked stereoselectivity in the inhibition of hepatobiliary transport of cardiac glycosides.
OBJECTIVE
Certain basic (cationic) drugs are known to interact with the hepatic transport, and renal and/or biliary clearance of cardiac glycosides. The mechanisms behind these interactions are not fully understood. In the present study our aim was to investigate the effects of the two diastereomers, quinidine and quinine, as well as the calcium antagonist verapamil, on the hepatobiliary elimination of digoxin and ouabain in the isolated perfused rat liver.


METHODS
Livers from male, fasting Wistar rats were perfused by recirculation of Krebs-Henseleit bicarbonate buffer supplemented with 1% BSA. Disposition of digoxin or ouabain was studied at an initial perfusion medium concentration (Ci) of 100 or 10 nmol/l for digoxin and a Ci of 30 micromol/l for ouabain. The Ci of quinine, quinidine or verapamil was 50 micromol/l. Concentrations of the drugs in perfusion medium and bile were followed up to 2 h.


RESULTS
A marked reduction in the initial medium disappearance rate of digoxin and ouabain by quinine was found, whereas quinidine did not affect the hepatic disposition of the cardiac glycosides. The stereoselective inhibition of digoxin and ouabain clearance by quinine, and not by quinidine, was shown to be due to an effect on the hepatic uptake level rather than on the metabolic conversion and/or the biliary excretion steps. An allosteric type of inhibition by the basic drugs, exerted from the inside of the cells, is inferred. This interaction may occur at the sinusoidal plasma membrane on the level of multi-specific carrier proteins for cardiac glycosides and cationic drugs, as cloned recently by various groups.


CONCLUSIONS
A marked stereoselective difference was found in the effect of the stereoisomers quinidine and quinine on the hepatic uptake of digoxin and ouabain, quinine being the potent inhibitor.
Hedman
A
A
Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, Groningen Institute of Drug Studies, The Netherlands.
Meijer
D K
DK
D000818:Animals; D001659:Biliary Tract / Q000187:drug effects* / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002301:Cardiac Glycosides / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000378:metabolism*; D004077:Digoxin / Q000378:metabolism; D004347:Drug Interactions; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D010042:Ouabain / Q000378:metabolism; D011802:Quinidine / Q000494:pharmacology*; D011803:Quinine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D002301:Cardiac Glycosides; D002316:Cardiotonic Agents; D010042:Ouabain; D004077:Digoxin; D011803:Quinine; D014700:Verapamil; D011802:Quinidine