Title

Mechanisms Underlying the Digoxin-Quinidine Interaction

Date of Award

5-1-1982

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neurology

Abstract

The clinically relevant interaction between quinidine and digoxin was investigated using unanesthetized and unrestrained guinea pigs for in vivo pharmacokinetic and tissue disposition as well as in vitro [’H]-digoxin binding studies using brain region preparations from dog, guinea pig and rat. Quinidine (3 mg/kg) caused significant elevation of plasma levels of digoxin as early as 5 minutes post-injection and the increase persisted for at least 8 hours. Significant decrease (20%) in the volume of distribution of digoxin was observed in quinidine treated animals. The decreased volume of distribution appeared to be due to displacement of digoxin from tissue stores by quinidine as evidenced by decreased tissue to plasma ratios for kidney (41%), intestine (41%), fat (33. -ung (31%), left ventricle (27%), liver (24%), left atrium (22%), right ventricle (21%), right atrium (18%), pancreas (12%), and bladder (4%) samples.

Crude synaptic membrane preparations were isolated from hypothalamus, hippocampus, brain stem, midbrain, cerebellum, striatum, and frontal cortex from dog, guinea pig, and rat brains. The in vitro binding of .3 [ H]-digoxin was specific, saturable and dependent on time, temperature, I [ 2 Mg and ATP. Other cardiac glycosides competed for [ H]-digoxin binding sites with high affinity, while central nervous system agonists and antagonists did not. Scatchard-type plots revealed a single species of binding sites with dissociation constants ranging from 3.0 to 35.8 nM and apparent maximal number of binding sites varying from 0.9 to 12.2 p moles/mg protein. Quinidine (10, 50, 100 pM) caused dose dependent 3 inhibition of [*H]~digoxin binding in brain region preparations and maximum decrease was observed in dog cerebellum, guinea pig and rat striatum. Such a competition was stereospecific since quinine, the 1-isomer of quinidine, did not affect the binding. Sodium azide and 2,4-dinitrophenol increased binding in brain preparations.

These studies support the hypothesis that quinidine increases plasma levels of digoxin by displacing digoxin from generalized tissue storage sites and from less active to more active binding sites in brain. These effects may presumably account for the increased toxicity observed in patients exposed to digoxin-quinidine interaction.

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