The effect of phenytoin on the tissue concentrations of digoxin in the rat

Rats treated chronically with digoxin were treated with two different dose levels of phenytoin, either as a single dose or chronically. Digoxin concentrations were measured by radioimmunoassay in the serum, urine, heart, muscle, liver, and the kidney. Chronic treatment with the high dose of phenytoin significantly increased the digoxin levels in the serum and tissues and decreased the renal clearance of digoxin. The low dose of phenytoin significantly reduced the serum and tissue levels of digoxin and increased the renal clearance. Single doses of phenytoin had a tendency to cause similar changes. Levels of digoxin were altered during the phenytoin treatment. In contrast to man, digoxin is extensively metabolized in the rat. Enzyme induction in connection with low phenytoin dosage and inhibition by high dosage is the suggested mechanism. It can be speculated that the tissue distribution and excretion of digoxin are altered.