The stereoisomers quinine and quinidine exhibit a marked stereoselectivity in the inhibition of hepatobiliary transport of cardiac glycosides

doi:10.1016/0168-8278(88)80011-4

Journal of Hepatology

Volume 28, Issue 2, February 1998, Pages 240-249

https://doi.org/10.1016/0168-8278(88)80011-4 Get rights and content

Abstract

Background/Aims: 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 (C_i) of 100 or 10 nmol/l for digoxin and a C_i of 30 μmol/l for ouabain. the C_i of quinine, quinidine or verapamil was 50 μmol/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.

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The stereoisomers quinine and quinidine exhibit a marked stereoselectivity in the inhibition of hepatobiliary transport of cardiac glycosides

Abstract

Methods Enzymol

Life Sci

J Pharm Sci

J Hepatol

Biochem Pharmacol

Adv Drug Deliv Rev

Effect of quinidine on plasma concentrations of digoxin

Br Med J

Digoxin-quinidine interaction. Pharmacokinetic evaluation

N Engl J Med

Effect of quinidine on plasma concentration and renal clearance of digoxin. A clinically important drug interaction

Br J Clin Pharmacol

Quinidine reduces biliary clearance of digoxin in man

Eur J Clin Invest

Interactions in the renal and biliary elimination of digoxin: stereoselective difference between quinine and quinidine

Clin Pharmacol Ther

Digoxin-verapamil interaction: reduction of biliary but not renal digoxin clearance in humans

Clin Pharmacol Ther

Transport of drugs, proteins and drug-protein conjugates

Organische Sorptionsmittel

Metabolism of cardiac glycosides studied in the isolated perfused guinea-pig liver

Br J Pharmacol