| Popis: |
Some aspects of the in vivo disposition of [3H]doxorubicin were investigated in mice in the first 6 hr after a 5 mg/kg i.v. dose. The disappearance of radioactivity from plasma and erythrocytes was consistent with biphasic kinetics. Highest peak radioactivity was found in lung, liver and kidney. Retention half-lives of radioactivity in heart, lung, kidney and small intestine were between 4.5 to 6.5 hr, while in liver, adrenal gland and spleen they were 7 to 13 hr and in skeletal muscle and bone marrow were 17 and 35 hr, respectively. Radioactivity in pancreas and epididymal fat had not equilibrated by 6 hr, and brain and testicle contained little radioactivity. Exhaustive methanol-ether extraction of acid-precipitated homogenates showed covalent binding of radioactivity to lung, liver, kidney and spleen at 40 to 100 pmol/mg of protein, while binding in plasma, small intestine and pancreas ranged from 4 to 30 pmol/mg of protein; heart and skeletal muscle showed 0 to 1.4 pmol/mg of protein at all times examined. Differential centrifugation revealed no site of subcellular accumulation within liver, kidney or most notably heart, other than the nuclear fraction. Specific levels of drug were highest in nuclei of liver, requiring 45 min to reach peak amounts; the lowest quantity per milligram of nuclear protein was found in the heart, and had already peaked by 10 min. These results suggest that the cardiotoxicity of doxorubicin may not be due to concentration or retention of drug within heart tissue as a whole or any non-nuclear subcellular fraction of it nor to the covalent binding of drug to heart protein, but may follow directly from the interaction of doxorubicin with the cardiac nuclei. |
