Tissue digoxin concentrations during the quinidine-digoxin interaction

Tissue digoxin concentrations during the quinidine-digoxin interaction

EXPERIMENTAL STUDIES Tissue DigoxinConcentrationsDuringthe Quinidine-DigoxinInteraction NATALIE J. WARNER, MD, EDWARD B. LEAHEY Jr., MD, THOMAS J. HO...

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EXPERIMENTAL STUDIES

Tissue DigoxinConcentrationsDuringthe Quinidine-DigoxinInteraction NATALIE J. WARNER, MD, EDWARD B. LEAHEY Jr., MD, THOMAS J. HOUGEN, MD, J. THOMAS BIGGER Jr., MD, and THOMAS W. SMITH, MD

Digoxin concentrations in serum, myocardium, 3 separate skeletal muscles, kidney, liver, and 5 sites in the brain were measured in 26 dogs given 12alpha 3H-digoxin. Ten of the dogs also received 200 mg of quinidine sulfate orally 3 times daily for 3 days, and 6 others received 240 mg of quinidine gluconate intravenously every 3 hours for 24 hours. Mean serum quinidine concentration was 6.7 f 1.5 pg/ml in the dogs treated with quinidine for 24 hours and 3.6 f 2.3 in the dogs treated with quinidine for 3 days (p
received quinidine for 24 hours. In this group, the ratio of myocardial-to-serum digoxin concentration was higher (p
The serum digoxin concentration is used to infer cardiac concentrations of digoxini and probable effects of digoxin on cardiac rhythm and contractility.2,3 When

quinidine is given with digoxin, the serum digoxin concentration increases as a result of decreases in digoxin clearance and volume of distribution.4ms Displacement of digoxin from binding sites in tissue, including myocardium, has been suggested as the mechanism of the quinidine-induced decrease in digoxin volume of distribution.4-6Te In order to manage patients receiving both digoxin and quinidine, it is important to know whether the relationship between serum digoxin concentration and myocardial digoxin concentration and effect is changed by quinidine. Previous studies of the effects of quinidine on tissue concentrations of digoxin include a study of skeletal muscle digoxin concentration in patients and 2 studies done in animals. Schenck-Gustafsson et allo reported that the ratio of skeletal muscle-to-serum concentration of digoxin decreased in 8 of 10 patients after 4 days of

From the Departments of Medicine and Pharmacology, Columbia University College of Physicians and Surgeons, New York, New York, and the Cardiovascular Division, Brigham and Women’s Hospital, the Department of Cardiology, Children’s Hospital Medical Center, and the Departments of Medicine and Pediatrics, Harvard Medical School, Boston, Massachusetts. This study was supported in part by Grants K-26653, HL-24302, and HL-18003 from the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Public Health Service, Bethesda, Maryland; a grant from the John Sable Heart Fund, Rochester, New York; and a grant-in-aid from Burroughs Wellcome, Research Triangle Park, North Carolina. Manuscript received December 22, 1982; revised manuscript received February 22, 1983, accepted February 25, 1983. Address for reprints: J. Thomas Bigger Jr., MD, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032.

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quinidine treatment. The decrease in skeletal muscle digoxin concentration completely accounted for the observed decrease in digoxin volume of distribution. Kim et al”J” gave intravenous tritiated digoxin to guinea pigs with and without simultaneous quinidine infusion. The serum digoxin concentration in animals given quinidine was higher than that of animals infused with digoxin alone, indicating that quinidine decreased the tissue uptake of digoxin. Doherty et all” gave tritiated digoxin to 11 dogs, 6 of which also received quinidine. The concentration of digoxin in the myocardium was lower in the quinidine-digoxin group than in the digoxin group. The mean serum digoxin concentration of the quinidine-digoxin group was also lower and there was no difference in the myocardial-to-serum digoxin concentration ratio. The present study determines the effect of quinidine on tissue digoxin concentrations and on the ratio of tissue digoxin concentration-to-serum digoxin concentration in dogs.

Methods Experimental preparation: Digoxin specifically labelled at the la-alpha position with 0.2 PCi of tritium per microgram of digoxin was given to 26 mongrel dogs of either sex (14 to 27 kg) in doses of 40 pglkg intravenously on day 1 and 20 pg/kg intravenously on days 2 and 3. Ten of the dogs received only digoxin. Ten received digoxin plus quinidine sulfate, 200 mg orally 3 times per day for the 3 days of the study. We used these regimens because preliminary studies in our laboratory showed that they produced steady-state serum drug concentrations. In an attempt to achieve higher and more predictable

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FIGURE 1. Serum digoxin and serum quinidine concentrations for each group of experimental animals. Dogs that received digoxin only are represented by circles and labelled D. Dogs that received digoxin and quinidine for 3 days are represented by crosses and labelled D + Q3, and dogs that received digoxin for 3 days and quinidine for 24 hours are represented by triangles and labelled D + Ql. Dogs that received intravenous quinidine for 24 hours had a mean serum quinidine concentration of 6.7 f 1.5 pg/ml, which was significantly higher (p
serum quinidine concentrations and to investigate the tissue digoxin concentration in the early phase of the quinidinedigoxin interaction, we gave 6 additional dogs 240 mg of quinidine gluconate intravenously every 3 hours for 24 hours after the third and final dose of digoxin. Tissue samples were obtained on day 4, 18 to 24 hours after the final dose of digoxin. Tissue analysis: Serum samples were obtained from each dog immediately before it was killed. Three samples of approximately 50 mg each were obtained from the myocardium, 3 separate skeletal muscles (occipital, intercostal, and quadriceps femoris), kidney, liver, cerebral cortex, cerebellum, hypothalamus, pons, and medulla. Tissue samples were blotted dry, weighed, and dissolved by overnight incubation at 45°C in 0.5 ml of ProtosolTM(New England Nuclear). Glacial acetic acid (0.02 ml) was added to each sample to make it less alkaline. After addition of scintillation medium (TT21, Yorktown Research), the samples were stored in the dark at 4°C for 1 week to reduce chemiluminescence. Duplicate samples of 500 ~1 of serum were added to scintillation medium and also stored in the dark for 1 week. Samples were counted in a liquid scintillation counter until there was no difference between 1 set of counts and the next, indicating that there was no remaining chemiluminescence. To permit correction for quenching, an internal standard containing approximately 5,000 cpm of tritiated digoxin was added to each sample and samples were again counted until there was no difference in counts per minute on successive determinations. By comparison with the counts per minute obtained from a known concentration of tritiated digoxin, the tissue or serum digoxin concentration was calculated in nanograms per gram of wet tissue weight or nanograms per milliliter of serum. The average digoxin concentration of the 3 samples from each tissue was calculated for each dog and used in the statistical analysis. Serum quinidine concentration was measured by high pressure liquid chromatography after extraction by the method of Cramer and Isaksson.14 Statistical analysis: The ratio of tissue-to-serum digoxin concentration was calculated by dividing tissue digoxin concentration by the dog’s serum digoxin concentration. Means and standard deviations of serum and tissue digoxin concentrations and of the tissue-to-serum digoxin concentration ratios were calculated for each tissue in all 3 groups of dogs. Student’s t test was used to compare the mean serum quinidine concentrations of the 2 groups of dogs that received quinidine and to compare the mean serum digoxin concentration of each of the quinidine-treated groups to the mean serum digoxin concentration of the group that received digoxin alone. Hotelling’s t test, a multivariate t test designed to avoid the possibility of making type I statistical errors by performing repeat r tests,ls was used to compare tissue concentrations of digoxin between each of the groups of dogs that received quinidine and the group that received digoxin alone. Regression analysis was used to correlate serum digoxin concentration and tissue-to-serum digoxin concentration ratios with serum quinidine concentrations.

Results Serum digoxin and quinidine concentrations: Serum quinidine and digoxin concentrations for the experimental animals are shown in Figure 1. The mean serum quinidine concentration was 3.6 f 2.3 ,ug/ml (mean f standard deviation) in the group that received 3 days of oral quinidine and 6.7 f 1.5 pg/ml in the dogs that received intravenous quinidine for 24 hours. Despite the wide between-animal variability in the group

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that received oral quinidine, these values are significantly different at the p CO.01 level. Unexpectedly, no difference was found in the mean serum digoxin concentration between either group of dogs that received quinidine and the group that received only digoxin. The 10 dogs that received digoxin alone had a mean serum digoxin concentration of 2.72 f 0.88 ng/ml. The average serum digoxin concentration in the 6 dogs that received digoxin and quinidine for 24 hours was 2.61 f 0.45 ng/ml. The dogs that received quinidine sulfate for 3 days had an average serum digoxin concentration of 3.20 f 0.92 ng/ml. Despite the fact that the mean is higher in this group than in either of the other 2 groups, there was wide between-animal variability in serum digoxin concentration in this group and there was no statistically significant difference between the mean serum digoxin concentration of this group and the mean serum digoxin concentration of the group that received digoxin only. Figure 2 shows the relationship of serum digoxin concentration to serum quinidine concentration for the 10 dogs that received digoxin and 3 days of quinidine. There is a positive linear regression of serum digoxin concentration on serum quinidine concentration, indicating that a drug interaction between quinidine and digoxin occurred. No such relationship was seen between serum quinidine concentrations and serum digoxin concentrations in the dogs that received 24 hours of quinidine. Tissue digoxin concentrations: Table I shows the mean tissue digoxin concentration for each tissue type in the 3 groups of dogs. The tissue digoxin concentration varied widely from tissue to tissue. Kidney tissue samples had the highest digoxin concentration, followed by the heart, liver, skeletal muscle, and brain samples. We found no statistically significant differences in mean tissue digoxin concentrations between either of the 2 groups of dogs treated with quinidine and the group treated with digoxin alone. Table I also shows the ratios of tissue-to-serum digoxin concentration for each tissue in the 3 experimental groups. Similar ratios of tissue-to-serum digoxin TABLE I

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FGUAE 2. Serum digoxin conCMkatkm plotted against serum q&MirIe concentraticn as the independent Variable for the 10 dogs that received 3 days of quinidine. The correlation coefficient for these 2 variables is 0.76 (p
concentration have been reported in animals and patients treated with digoxin. 16-19We found no significant differences in these ratios between dogs that received digoxin alone and those that received digoxin and quinidine for 3 days. However, there were differences in the ratio of tissue-to-serum digoxin concentration between the dogs that received digoxin alone and dogs that received digoxin and 1 day of intravenous quinidine. Using Hotelling’s t test, which simultaneously tests the equality of the means of several variables, the chance that the tissue-to-serum ratios for the digoxin only and the digoxin and 24-hour quinidine group were equal was p CO.01. (We used a critical value of p <0.05/2 = p <0.025 because we did 2 separate Hotelling’s t tests.) Further analysis showed that there were differences between the 2 groups in 4 of the tissue-to-serum digoxin concentration ratios. Myocardial-to-serum digoxin concentration ratio was higher in dogs that received quinidine for 24 hours than in dogs that received digoxin only (p
Tissue Digoxin Concentrations and Tissue-Serum Concentration Ratios Tissue Digoxin (rig/g Wet Weight)

Heart Kidney Skeletal muscle Quadriceps Occipital Intercostal Brain Cortex Cerebellum Pons Hypothalamus Medulla Liver ‘ p
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FWURE 3. Ttw ratio of renal-to-serumdigoxinconcentrationplotted on the ordinateas the dependentvariableagainstthe serum quinidine concentrationas the independentvariableon the abscissafor all of the dogsthat received quinidine.Dogs that received quinidinefor 3 days are representedby cresws. Dogsthat receivedquinidinefor 24 hours we repmsentedby blmgle& The conelationcoeffkii betweenthese 2 variablesis -0.63 (p <0.05). D + Ql = digoxinfor 3 daysand quinidinefor 24 hours;D + 03 = digoxinand quinidinefor 3 days.

We performed regression analysis on concentration ratio for these 4 tissues using serum quinidine concentration as the independent variable. There was no correlation between serum quinidine concentration and the ratio of tissue-to-serum concentration of digoxin for myocardial, skeletal muscle, or medullary brainstem. Figure 3 shows the relationship between renal-to-serum digoxin ratio and serum quinidine concentration. As the serum quinidine concentration increased, the ratio of renal to serum digoxin concentration decreased (r = -0.63, p <0.05). Discussion Despite the fact that we could not demonstrate a statistically significant difference in mean serum digoxin concentration between either of the groups of dogs that received quinidine and the group that received digoxin only, we have evidence for the existence of a quinidine-digoxin interaction in both of these groups. Previous studies have shown a relationship between serum quinidine concentration and the magnitude of the effect of quinidine on serum digoxin concentration.17 In the group of dogs that received quinidine for 3 days, regression analysis with serum quinidine concentration as the independent variable and serum digoxin concentration as the dependent variable (Fig. 2) showed a regression (serum digoxin concentration = 2.1 + 0.31 X serum quinidine concentration). Differences in tissue digoxin concentrations between the group of dogs that was treated with quinidine for 24 hours and the group treated with digoxin only was evidence that the quinidine-digoxin interaction was occurring after 24 hours of quinidine administration. We did not confirm the findings of Doherty et a1,13 who reported that the concentration of digoxin in the myocardium was lower and the concentration of digoxin in the brain was higher in dogs that received digoxin and

quinidine than in dogs that received digoxin only. Interpretation of both our study and that of Doherty et al is limited by the lack of a statistically significant difference in serum digoxin concentration between dogs treated with digoxin and quinidine and dogs treated with digoxin alone. We did find that the dogs that received 24 hours of high-dose intravenous quinidine (but not those that received 3 days of quinidine) had a statistically significantly higher ratio of myocardial-toserum digoxin concentration than did the dogs that received digoxin only. Further work is necessary to determine the explanation for this finding. Skeletal muscle accounts for 40 to 50% of the body digoxin stores in both dogs and humans.1°J7 A small change in the concentration of digoxin in the skeletal muscle would decrease the volume of distribution of digoxin sufficiently to explain the change in serum digoxin concentration seen with quinidine.10 Neither of our quinidine regimens produced an increase in serum digoxin concentration (we did not directly measure volume of distribution) and we are unable to support the hypothesis that quinidine decreases digoxin volume of distribution and thereby increases serum digoxin concentration by displacing digoxin from skeletal muscle. Quinidine causes a decrease in the renal clearance of digoxin, which occurs within hours of quinidine administration.5-sJa20 We measured the concentration of digoxin in the kidney after 24 hours of quinidine administration and found that it is less than expected based on the serum digoxin concentration. This finding suggests that decreased binding or uptake of digoxin by renal tubular cells, rather than a block in excretion of digoxin present in the kidney, accounts for the quinidine-induced decrease in renal clearance of digoxin. Previous studies have shown that the quinidine-induced decrease in the renal clearance of digoxin is quinidine dose-dependent. 7 When all 16 dogs that received quinidine in this study are considered together, there is a significant negative correlation between serum quinidine concentration and the ratio of renal-to-serum digoxin concentration. In summary, this study reports the tissue concentrations and tissue-to-serum concentration ratios of digoxin during the quinidine-digoxin interaction in dogs. After drug doses calculated to produce steadystate serum drug concentrations, there were no differences in tissue digoxin concentrations or tissue-to-serum digoxin concentration ratios between dogs treated with quinidine and dogs treated with digoxin alone. Specifically, in contrast to a previous study,13 we found no evidence that myocardial digoxin concentration was lower or brain digoxin concentration was higher with quinidine. In dogs that received 24 hours of intravenous quinidine, the ratio of myocardial digoxin concentration-to-serum digoxin concentration was higher and the ratios of renal, medullary brainstem, and occipital muscle-to-serum digoxin concentration were lower than in dogs that received digoxin only. The mechanism of the quinidine-digoxin interaction remains to be delineated further in studies in which the serum digoxin concentration increases substantially during quinidine treatment.

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Acknowledgmenti We thank preparation of the figures.

Zena Toran

for expert

References 1. Malcolm A, Coltart J. Relation between concentrations of digoxin in the myocardium and in the plasma. Br Heart J 1977;39:935-938. 2. Barr I. Smith TW, Klein MD, Hagemeijer F, Lown 8. Correlation of the electrophysiologic action of digoiin wiih serum digoxin concentration. J Pharmacol Exp Ther 1972;180:710-722. Shaplro W, Narahara K, Tauberf K. Relationship of plasma digitoxin and 3. digoxin to cardiac response following intravenous digitalization in man. Circulation 1970;42:1065-1072. 4. Leahey ES, Reiffel JA, Giardiana EG, Blgger JT. The effect of quinidine and other oral antiarrhythmic drugs on serum digoxin. Ann Intern Med 1980:92%05-608 5. Hager WD, Fenster P, Mayersohn 1111, Perrier D, Graves P, Marcus FI, Goldman S. Diqoxin-ouinidine interaction. N Enql J Med 1979;300: 1238-1241. 6. Schenck-Gustalsson K, Dahlqvisl R. Pharmacokinetics of digoxin in patients subjected to the quinidinedigoxin interaction. Br J Clin Pharmacol 1981; 11:181-186. 7. Leahey ES, Bigger JT, Butler VP, Reiflel Jt, O’Connell GC, Scaffidi LE, Rottman JN. Quinidinedigoxin interaction: trme course and pharmacokinetics. Am J Cardiol 1981;48:1141-1146. a. Ochs HR, Bodem G, Greenblatt DJ. Impairment of digoxin clearance by coadministration of ouinidine. J Clin Pharmacol 1981:21:396-400. 9. Klm D, Akera T, Bror& TM. Tissue binding sites involved in quinidinecardiac

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glycoside interactions. J Pharmacoi Exp Ther 1981;218:357-362, IO. Schenck-Gustatsson K, Jogestrand ?, Nordlander R, Dahlqvist R. Effect of quinidine on digoxin concentration In skeletal muscle and serum in patients with atrial fibrillation. N Engl J Med 1981;305:209-211. Il. Kim D, Akera T, Brody TM. Effects of quinidine on the cardiac glycoside sensitivitv of ouinea-oia and rat heart. J Pharmacol Exp Ther 1981;217: 559-565: ” 12. Kim D! Akera T, Brody TM. Interactions between quinidine and cardiac glycosldes involving mutual binding sites in the guinea pig. J Pharmacol Exp Ther 1981;218:108-114. 13. Doherty JE, Straub KD, Murphy ML, deSoyza N, Bissett JK, Kane JJ. Digoxin-quinidine interaction: changes in canine tissue concentration from steady state with quinidine. Am J Cardiol 1980;45: 1196-1200. 14. Cramer G, lsaksson 8. Quantitative determination of quinidine in plasma. Stand J Clin Lab Invest 1963;15:553-556. 15. Finn JD. A General Model for Multivariate Analysis. New York: Holt, Rhinehart and Winston, 1974:150-155. 16. Doherty JE, Perkins WH, Flantgan WJ. The distribution and concentration of tritiated digoxin in human tissues. Ann Intern Med 1967;66:116-124. 17. Jogestrand T, Sundqvist K. Skeletal muscle digoxin concentration and its relation to serum digoxin concentration and cardiac effect in healthy man. Eur J Clin Pharmacol 1981;19:89-95. 18. Dahlqvist R, Ejvinsson G, Schenck-Gustafsson K. Effect of quinidine on plasma concentration and renal clearance of digoxin. A clinically important drug interaction. Br J Clin Pharmacol 1980;9:413-418. 19. Jogestrand T. Digoxin concentration in right atrial myocardium, skeletal muscle. and serum in man: influence of atrial rhvthm. Eur J Clin Pharmacol 1980;17:243-250. 20. Leahey EB Jr, Carson JA, Bigger JT Jr. Reduced renal clearance of digoxin during chronic quinidine administration (abstr). Circulation 1979;6O:Suppl II 11-16.