Altered tissue digoxin uptake after a toxic dose

Tissue distribution and left ventricular (LV) effects of digoxin were studied after intravenous administration of low and high doses to dogs. LV dP/dt was increased by 0.03 mg/kg digoxin in nine, group A, and digoxin-induced arrhythmias or death occurred after 0.14 mg/kg in nine others, group B. Two hours after dosing during the slow excretion phase confirmed by serial serum sampling, the animals were killed. Serum and tissue extract digoxin determinations were performed by radioimmunoassay. Digoxin levels in group A were serum 3.9 ng/ml, kidney 428 ng/gm wet wt, liver 41, pancreas 39, diaphragn 21, apex, freewall, and septum LV 117-122, right ventricle (RV) 105, left atrium (LA) 51, right atrium (RA) 50, and the serum to apex LV ration was 1:32. The tissue contents and distribution were similar to previous [3H]digoxin data. The concentrations were higher in B; for all p less than 0.001. The toxic to therapeutic concentration ratios were serum 10, kidney 2.8, liver 5.5. pancreas 5,4, diaphragm 6.5, LV 4.3, RV 4.0, LA 3.5, RA 3.4. The serum to LV ratio was lower at 1:13, p less than 0.001. Myocardial toxicity was associated with marked but apparently limited increases in tissue digoxin content in this preparation. The disproportionately high serum level suggests paralysis or saturation of kidney and other tissue binding resulting in lower serum to tissue concentration ratios. Whenever serum to tissue ratios vary from expected values, serum digoxin levels may not be linearly related to tissue content or cardiac effects.