Tissue-serum correlates of digoxin-amiodarone pharmacokinetic interaction in rats: evidence for selective tissue accumulation and reduced tissue binding

The pharmacokinetic interaction between digoxin (1) and amiodarone (2) has drawn increasing attention during recent years, but the tissue correlates of such an interaction are not known. This issue was therefore investigated in three groups of Sprague-Dawley rats. When 1 alone was given (250 micrograms/d), the serum concentration of 1 was 0.88 +/- 0.36 ng/mL; when 1 was combined with 2 (66 mg/kg/d), the level of 1 was 2.62 +/- 1.23 ng/mL (p less than 0.05) and was 5.49 +/- 1.07 ng/mL (p less than 0.05) when the dose of 2 was 132 mg/kg/d. These increases correlated with the serum levels of 2 and the deethyl metabolite 3. The myocardial level of 1 was 29.40 +/- 1.34 ng/g without 2; after a low dose of 2, it was 35.80 +/- 7.52 ng/g (nonsignificant) and, after a high dose, it was 42.80 +/- 7.20 (p less than 0.05). In skeletal muscle, the level of 1 was 22.50 +/- 14.7 ng/g without 2, 41.00 +/- 2.45 ng/g (p less than 0.05) after a low dose, and 77.60 +/- 17.45 ng/g (p less than 0.05) after a high dose. The corresponding values for the brain were 32.20 +/- 5.60 ng/g, 48.20 +/- 7.60 ng/g (p less than 0.05), and 60.90 +/- 11.00 ng/g (p less than 0.05). The tissue-serum ratios for 1 in all three tissues were reduced by 2, suggesting a decrease in the tissue binding of the glycoside. There was less uptake of 1 in the myocardium compared with uptake in the skeletal muscle and brain.(ABSTRACT TRUNCATED AT 250 WORDS)